Two major causes of human aging include protein misfolding and free radicals. Protein misfolding occurs when proteins which are synthesized by cells do not have the proper amino acid sequence or do not achieve the cor...Two major causes of human aging include protein misfolding and free radicals. Protein misfolding occurs when proteins which are synthesized by cells do not have the proper amino acid sequence or do not achieve the correct three-dimensional configuration to function properly. Peer-reviewed scientific literature explains how these processes contribute to many age-associated diseases. A few examples include cancer, heart disease, dementias including Parkinson’s and Alzheimer’s </span><span style="font-family:Verdana;">diseases, and arthritis. This article reviews how protein misfolding can be slowed and even reversed by appropriate nutrition, potentially slowing and reversing these diseases. One cause of misfolding is mRNA translation occurring too rapidly for proper chaperone binding or protein folding. A second cause is deficiency of amino acids so improper tRNA binding occurs. A third cause is free radicals. They cause mutations promoting misfolding and cancer, and oxidize lipoproteins causing plaque in circulation promoting heart disease and stroke. Nutrients with proven actions will contribute to longer healthspans for our aging population. Healthspan is the number of healthy years before chronic or terminal diseases substantially impair the quality of life. This can be done especially by slowing and reversing these three causes of PM. Niacin, quercetin, EGCG, alpha-lipoic acid, N-acetyl-carnitine, tyrosine and cysteine address protein misfolding. Vitamin C and glutathione trap free radicals. Vitamin K amplifies free radical cancer killing by vitamin C and activates decalcification enzymes which remove calcium deposits in the circulatory system and strengthen bones. Apigenin activates the pathway of caloric restriction and induces cancer cell apoptosis. This article provides citations and explanations of the progress showing new ways to maintain health as we age. For convenience and cost savings, many of these ingredients can be consumed in supplement form, taken twice a day to maintain water-soluble nutrient levels.展开更多
Klebsiella has been considered as initiator of AS(ankylosing spondylitis)for nearly four decades.This study aimed to demonstrate that Klebsiella triggers ERS(endoplasmic reticulum stress)and HLA-B27 heavy chain misfol...Klebsiella has been considered as initiator of AS(ankylosing spondylitis)for nearly four decades.This study aimed to demonstrate that Klebsiella triggers ERS(endoplasmic reticulum stress)and HLA-B27 heavy chain misfolding.CA46 cells or splenocytes obtained from wild-type,MyD88/or TLR9/mice were stimulated with KP(Klebsiella pneumoniae)or its components including CPS(capsule polysaccharide),LPS(lipopolysaccharide),and KP gDNA(genomic deoxyribonucleic acid)respectively for 24 h and 48 h.The activation of ERS-related signaling was detected by Western blotting or RT-PCR,and the level of misfolded HLA-B27 was determined by non-reducing protein gel electrophoresis and Western blotting.The protein expression of BiP/Grp78 and calreticulin,the alternative splicing of XBP-1 mRNA(messenger ribonucleic acid),and the activation of caspase-12 and p38 were increased in a dose-dependent manner in HLA-B27-expressing CA46 cells after treatment with decapsulated KP.We also demonstrate that the EP,S-inducing effects occur via the TLR(Toll-like receptor)/MyD88-dependent signaling pathway.Significantly,HLA-B27 misfolding was also detected in decapsulated KP-treated B27-expressing cells.These results suggest that the non-antigen-specific induction of ERS and B27 misfoiding through TLR/MyD88 signaling might promote KP antigen-initiated autoreactive responses via the presentation of misfolded B27,and that small-molecules targeting TLRs might have potential as novel therapeutic agents for AS.展开更多
With the gradual advancement of research methods and technologies,various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases.However,current descriptions of th...With the gradual advancement of research methods and technologies,various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases.However,current descriptions of these biological processes do not fully explain the onset,progression,and development of these conditions.Therefore,exploration of the pathogenesis of neurodegenerative diseases remains a valuable area of research.This review summarizes the potential common pathogeneses of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,Huntington’s disease,frontotemporal lobar dementia,and Lewy body disease.Research findings have indicated that several common biological processes,including aging,genetic factors,progressive neuronal dysfunction,neuronal death and apoptosis,protein misfolding and aggregation,neuroinflammation,mitochondrial dysfunction,axonal transport defects,and gut microbiota dysbiosis,are involved in the pathogenesis of these six neurodegenerative diseases.Based on current information derived from diverse areas of research,these biological processes may form complex pathogenic networks that lead to distinctive types of neuronal death in neurodegenerative diseases.Furthermore,promoting the regeneration of damaged neurons may be achievable through the repair of affected neural cells if the underlying pathogenesis can be prevented or reversed.Hence,these potential common biological processes may represent only very small,limited elements within numerous intricate pathogenic networks associated with neurodegenerative diseases.In clinical treatment,interfering with any single biological process has proven insufficient to completely halt the progression of neurodegenerative diseases.Therefore,future research on the pathogenesis of neurodegenerative diseases should focus on uncovering the complex pathogenic networks,rather than isolating individual biological processes.Based on this,therapies that aim to block or reverse various targets involved in the potential pathogenic mechanisms of neurodegenerative diseases may be promising directions,as current treatment methods that focus on halting a single pathogenic factor have not achieved satisfactory efficacy.展开更多
Background:Accumulatingα-synuclein(α-syn)aggregates in neurons and glial cells are the staples of many synucleinopathy disorders,such as Parkinson’s disease(PD).Since brain adenosine becomes greatly elevated in age...Background:Accumulatingα-synuclein(α-syn)aggregates in neurons and glial cells are the staples of many synucleinopathy disorders,such as Parkinson’s disease(PD).Since brain adenosine becomes greatly elevated in ageing brains and chronic adenosine A1 receptor(A1R)stimulation leads to neurodegeneration,we determined whether adenosine or A1R receptor ligands mimic the action of known compounds that promoteα-syn aggregation(e.g.,the amphetamine analogue 2-aminoindan)or inhibitα-syn aggregation(e.g.,Rasagiline metabolite 1-aminoindan).In the present study,we determined whether adenosine,A1R receptor agonist N^(6)-Cyclopentyladenosine(CPA)and antago-nist 8-cyclopentyl-1,3-dipropylxanthine(DPCPX)could directly interact withα-syn to modulateα-syn aggregation and neurodegeneration of dopaminergic neurons in the substantia nigra(SN).Methods:Nanopore analysis and molecular docking were used to test the binding properties of CPA and DPCPX withα-syn in vitro.Sprague-Dawley rats were administered with 7-day intraperitoneal injections of the A1R ligands and 1-and 2-aminoindan,and levels ofα-syn aggregation and neurodegeneration were examined in the SN pars compacta and hippocampal regions using confocal imaging and Western blotting.Results:Using nanopore analysis,we showed that the A1R agonists(CPA and adenosine)interacted with the N-terminus ofα-syn,similar to 2-aminoindan,which is expected to promote a“knot”conformation andα-syn misfolding.In contrast,the A1R antagonist DPCPX interacted with the N-and C-termini ofα-syn,similar to 1-aminoindan,which is expected to promote a“loop”conformation that preventsα-syn misfolding.Molecular docking studies revealed that adenosine,CPA and 2-aminoindan interacted with the hydrophobic core ofα-syn N-terminus,whereas DPCPX and 1-aminoindan showed direct binding to the N-and C-terminal hydrophobic pockets.Confocal imaging and Western blot analyses revealed that chronic treatments with CPA alone or in combination with 2-aminoindan increasedα-syn expression/aggregation and neurodegeneration in both SN pars compacta and hippocampus.In contrast,DPCPX and 1-aminoindan attenuated the CPA-inducedα-syn expression/aggregation and neurodegeneration in SN and hippocampus.Conclusions:The results indicate that A1R agonists and drugs promoting a“knot”conformation ofα-syn can causeα-synucleinopathy and increase neuronal degeneration,whereas A1R antagonists and drugs promoting a“loop”con-formation ofα-syn can be harnessed for possible neuroprotective therapies to decreaseα-synucleinopathy in PD.展开更多
Protein misfolding is a general causation of classical conformational diseases and many pathogenic changes that are the result of structural conversion.Here I review recent progress in clinical and computational appro...Protein misfolding is a general causation of classical conformational diseases and many pathogenic changes that are the result of structural conversion.Here I review recent progress in clinical and computational approaches for each stage of the misfolding process,aiming to present readers an outline for swift comprehension of this field.展开更多
Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen r...Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.展开更多
Studies have demonstrated the association between black carbon(BC)particles and elevated risk of cardiovascular disease.However,the mechanisms underlying this relationship remain unclear.This study aims to investigate...Studies have demonstrated the association between black carbon(BC)particles and elevated risk of cardiovascular disease.However,the mechanisms underlying this relationship remain unclear.This study aims to investigate the effects of BC exposure on gene expressions in mice myocardium.Mice were divided into 3 groups(phosphate buffer saline(PBS)group,C50 group(50μg BC)and C100 group(100μg BC)).RNA sequencing was employed to conduct transcriptome analysis on myocardium samples.The expression levels of candidate genes were verified by qRT-PCR.Western Blot and Immunohistochemistry techniques were utilized to evaluate the expression of heat shock protein 70(Hsp70).BC exposure can cause an increase in the level of cardiac I-1βand IL-6.Transcriptome analysis revealed 1027 differentially expressed genes(DEGs)in the C100 group compared with the PBS group.Gene Ontology(GO)enrichment analysis demonstrated that these DEGs were primarily enriched in misfolded protein binding,respiratory chain and ATP metabolic process.Additionally,Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis indicated significant enrichment of DEGs in pathwaysmainly related to prion disease,oxidative phosphorylation and reactive oxygen species.HSPA1A and HSPA1B,as Hsp70 family genes,were enriched in GO term of misfolded protein binding and prion disease pathway.Moreover,the expression of cardiac Hsp70 was significantly decreased in both BC groups and showed a negative association with pro-inflammatory factors expression.BC exposure has been shown to cause inflammatory injury and may induce protein misfolding.Notably,Hsp70 was a potential cardioprotective factor and target for BC pollution-related effects.展开更多
Cardiac amyloidosis(CA)is characterized by the deposition of the misfolded amyloid precursor proteins in the myocardium of the heart.The systemic form of CA is mainly caused by either the misfolded monoclonal immunogl...Cardiac amyloidosis(CA)is characterized by the deposition of the misfolded amyloid precursor proteins in the myocardium of the heart.The systemic form of CA is mainly caused by either the misfolded monoclonal immunoglobulin light chains(kappa and lambda)or transthyretin.[1]The clinical manifestations are mainly overlap with symptoms of other cardiovascular diseases mostly hypertrophic cardiomyopathy and heart failure.Some cases often overlooked and remains undiagnosed because of the atypical clinical manifestations,especially in the elderly.展开更多
There are two degradation systems in mammalian cells, autophagy/lysosomal pathway and ubiquitin-proteasome pathway. Proteasome is consist of multiple protein subunits and plays important roles in degradation of short-...There are two degradation systems in mammalian cells, autophagy/lysosomal pathway and ubiquitin-proteasome pathway. Proteasome is consist of multiple protein subunits and plays important roles in degradation of short-lived cellular proteins. Recent studies reveal that proteasomal degradation system is also involved in signal transduction and regulation of various cellular functions. Dysfunction or dysregulation of proteasomal function may thus be an important pathogenic mechanism in certain neurological disorders. This paper reviews the biological functions of proteasome in signal transduction and its potential roles in neurodegenerative diseases.展开更多
Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein,a type III intermediate filament protein expressed in astrocytes.Both early(infantile or juvenile)and a...Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein,a type III intermediate filament protein expressed in astrocytes.Both early(infantile or juvenile)and adult onsets of the disease are known and,in both cases,astrocytes present characteristic aggregates,named Rosenthal fibers.Mutations are spread along the glial fibrillary acidic protein sequence disrupting the typical filament network in a dominant manner.Although the presence of aggregates suggests a proteostasis problem of the mutant forms,this behavior is also observed when the expression of wild-type glial fibrillary acidic protein is increased.Additionally,several isoforms of glial fibrillary acidic protein have been described to date,while the impact of the mutations on their expression and proportion has not been exhaustively studied.Moreover,the posttranslational modification patterns and/or the protein-protein interaction networks of the glial fibrillary acidic protein mutants may be altered,leading to functional changes that may modify the morphology,positioning,and/or the function of several organelles,in turn,impairing astrocyte normal function and subsequently affecting neurons.In particular,mitochondrial function,redox balance and susceptibility to oxidative stress may contribute to the derangement of glial fibrillary acidic protein mutant-expressing astrocytes.To study the disease and to develop putative therapeutic strategies,several experimental models have been developed,a collection that is in constant growth.The fact that most cases of Alexander disease can be related to glial fibrillary acidic protein mutations,together with the availability of new and more relevant experimental models,holds promise for the design and assay of novel therapeutic strategies.展开更多
Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link b...Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link between different PMDs,including Alzheimer disease(AD)and type 2 diabetes(T2D),AD and Parkinson disease(PD),and AD and prion disease.Among them,AD and T2D are the most prevalent PMDs,affecting millions of people globally,while Ab and hIAPP are the causative peptides responsible for AD and T2D,respectively.Increasing clinical and epidemiological evidences lead to a hypothesis that the cross-seeding of Ab and hIAPP is more biologically responsible for a pathological link between AD and T2D.In this review,we particularly focus on(i)the most recent and important findings of amyloid cross-seeding between Ab and hIAPP from in vitro,in vivo,and in silico studies,(ii)a mechanistic role of structural compatibility and sequence similarity of amyloid proteins(beyond Ab and hIAPP)in amyloid cross-seeding,and(iii)several current challenges and future research directions in this lessstudied field.Review of amyloid cross-seeding hopefully provides some mechanistic understanding of amyloidogenesis and inspires more efforts for the better design of next-generation drugs/strategies to treat different PMDs simultaneously.展开更多
The misfolding and aggregation of a-synuclein is the general hallmark of a group of devastating neurodegenerative pathologies referred to as synucleinopathies,such as Parkinson’s disease,dementia with Lewy bodies,and...The misfolding and aggregation of a-synuclein is the general hallmark of a group of devastating neurodegenerative pathologies referred to as synucleinopathies,such as Parkinson’s disease,dementia with Lewy bodies,and multiple system atrophy.In such conditions,a range of different misfolded aggregates,including oligomers,protofibrils,and fibrils,are present both in neurons and glial cells.Growing expe rimental evidence supports the proposition that solu ble oligomeric assemblies,formed during the early phases of the aggregation process,are the major culprits of neuronal toxicity;at the same time,fibrillar confo rmers appear to be the most efficient at propagating among interconnected neurons,thus contributing to the spreading ofα-synuclein pathology.Moreover,α-synuclein fibrils have been recently repo rted to release soluble and highly toxic oligomeric species,responsible for an immediate dysfunction in the recipient neurons.In this review,we discuss the current knowledge about the plethora of mechanisms of cellular dysfunction caused byα-synuclein oligome rs and fibrils,both contributing to neurodegeneration in synucleinopathies.展开更多
The neurodegenerative polyglutamine diseases are caused various disease proteins. Although these mutant proteins are by an expansion of unstable polyglutamine repeats in expressed ubiquitously in neuronal and non-neur...The neurodegenerative polyglutamine diseases are caused various disease proteins. Although these mutant proteins are by an expansion of unstable polyglutamine repeats in expressed ubiquitously in neuronal and non-neuronal cells, they cause selective degeneration of specific neuronal populations. Recently, increasing evidence shows that polyglutamine disease proteins also affect non-neuronal cells. However, it remains unclear how the expression of polyglutamine proteins in non-neuronal cells contributes to the course of the polyglutamine diseases. Here, we discuss recent findings about the expression of mutant polyglutamine proteins in non-neuronal cells and their influence on neurological symptoms. Understanding the contribution of non-neuronal polyglutamine proteins to disease progres- sion will help elucidate disease mechanisms and also help in the development of new treatment options.展开更多
Introduction: As a chaperone, heat shock protein acts as central integrators of protein homeostasis in cell. The form of these functions is to help setting up a complex protein molecular fold (folded protein) in many ...Introduction: As a chaperone, heat shock protein acts as central integrators of protein homeostasis in cell. The form of these functions is to help setting up a complex protein molecular fold (folded protein) in many important settings, such as growth, differentiation, and the ability to live. It has become clear that the control system plays an important role if the folding process fails or an error occurs, causing folding abnormalities and targeted functionality to accumulate. The accumulation of faulty protein folding would harm cells and can result in death. Apparently, there is a correlation between protein folding error with various diseases, such as diabetes mellitus and cancer. Method: We examined protein levels in all samples using Dotblott with monoclonal antibody anti-Hsp40 and anti-Hsp70. Levels of the protein content was read using a densitometer. Modification of Dot Blot was as follows: treatment was conducted with 3 × SSC, added with 20 mL blocking solution, add with total protein samples of 10 mg/ml on nitrocellulose paper, prehybridized, incubated at 70° for 30 seconds, incubated at 70° for 30 seconds with primary antibody anti-Hsp40 or Hsp70 protein and then added with second antibody HRP anti-Hsp40 or Hsp70 protein, treated with 3 × SSC and visualized with TSA HRP, and then administered with streptavidin, biothynil tyramide, and, finally, added with chromogen (DAB) in a confined space. Result: From the analysis of the data using Manova test with Wilk’s Lambda, there were significant differences in the levels of Hsp40 between Benign Oral Lesion (mean 688.31 area) and OSCC (mean 1354.59 area) patients (p 0.070), there was also a highly significant difference in Hsp70 levels between patients who experienced Benign Oral Lesion (mean 529.82 area) and OSCC (mean 1346.32 area) patients (p 0.006). Conclusion: OSCC patients have increased Hsp70 levels, so it is possible that something is going wrong in protein folding. Errors in protein folding result in a new homeostasis or inhibition of apoptosis and increasing cell proliferation that triggers carcinogenesis. Hsp40 acts as co-chaperones.展开更多
Protein quality control involves many processes that jointly act to regulate the expression, localization, turnover, and degradation of proteins, and has been highlighted in recent studies as critical to the different...Protein quality control involves many processes that jointly act to regulate the expression, localization, turnover, and degradation of proteins, and has been highlighted in recent studies as critical to the differentiation of stem cells during regeneration. The roles of constitutively secreted extracellular chaperones in neuronal injury and disease are poorly understood. Extracellular chaperones are multifunctional proteins expressed by many cell types, including those of the nervous system, known to facilitate protein quality control processes. These molecules exert pleiotropic effects and have been implicated as playing important protective roles in a variety of stress conditions, including tissue damage, infections, and local tissue inflammation. This article aims to provide a critical review of what is currently known about the functions of extracellular chaperones in neuronal repair and regeneration and highlight future directions for this important research area. We review what is known of four constitutively secreted extracellular chaperones directly implicated in processes of neuronal damage and repair, including transthyretin, clusterin, α2-macroglobulin, and neuroserpin, and propose that investigation into the effects of these and other extracellular chaperones on neuronal repair and regeneration has the potential to yield valuable new therapies.展开更多
Amyotrophic lateral sclerosis is a neurodegenerative disease,and the molecular mechanism underlying its pathology remains poorly understood.However,inflammation is known to play an important role in the development of...Amyotrophic lateral sclerosis is a neurodegenerative disease,and the molecular mechanism underlying its pathology remains poorly understood.However,inflammation is known to play an important role in the development of this condition.To identify driver genes that affect the inflammatory response in amyotrophic lateral sclerosis,as well as potential treatment targets,it is crucial to analyze brain tissue samples from patients with both sporadic amyotrophic lateral sclerosis and C9orf72-related amyotrophic lateral sclerosis.Therefore,in this study we used a network-driven gene analysis tool,NetBID2.0,which is based on SJARACNe,a scalable algorithm for the reconstruction of accurate cellular networks,to experimentally analyze sequencing data from patients with sporadic amyotrophic lateral sclerosis.The results showed that the OSMR gene is pathogenic in amyotrophic lateral sclerosis and participates in the progression of amyotrophic lateral sclerosis by mediating the neuroinflammatory response.Furthermore,there were differences in OSMR activity and expression between patients with sporadic amyotrophic lateral sclerosis and those with C9orf72-related amyotrophic lateral sclerosis.These findings suggest that OSMR may be a diagnostic and prognostic marker for amyotrophic lateral sclerosis.展开更多
Prion diseases are a class of fatal neurodegenerative diseases caused by misfolded prion proteins.The main reason is that pathogenic prion protein has a strong tendency to aggregate,which easily induces the damage to ...Prion diseases are a class of fatal neurodegenerative diseases caused by misfolded prion proteins.The main reason is that pathogenic prion protein has a strong tendency to aggregate,which easily induces the damage to the central nervous system.Point mutations in the human prion protein gene can cause prion diseases such as Creutzfeldt-Jakob and Gerstmann's syndrome.To understand the mechanism of mutation-induced prion protein aggregation,the mutants in an aqueous solution are studied by molecular dynamics simulations,including the wild type,V180I,H187R and a double point mutation which is associated with CJD and GSS.After running simulations for 500 ns,the results show that these three mutations have different effects on the kinetic properties of PrP.The high fluctuations around the N-terminal residues of helix 2 in the V180I variant lead to a decrease in hydrogen bonding on helix 2,while an increase in the number of hydrogen bonds between the folded regions promotes the generation ofβ-sheet.Meanwhile,partial deletion of salt bridges in the H187R and double mutants allows the sub-structural domains of the prion protein to separate,which would accelerate the conversion from PrPC to PrPSc.A similar trend is observed in both SASA and Rg for all three mutations,indicating that the conformational space is reduced and the structure is compact.展开更多
A myloidopathy is one of the most prominent hallmarks of Alkheimer's disease(AD),the leading cause of dementia worldwide,and is characterized by the accumulation of amyloid plaques in the brain parenchyma.The plaq...A myloidopathy is one of the most prominent hallmarks of Alkheimer's disease(AD),the leading cause of dementia worldwide,and is characterized by the accumulation of amyloid plaques in the brain parenchyma.The plaques consist of abnornal deposits mainly composed of an aggregation-prone protein fragment,B-amyloid 140/1-42,into the extracellular matrix.Brillouin micro-spectroscopy is an all-optical contactless technique that is based on the interaction between visible light and longitudinal acoustic waves or phonons,giving access to the viscoelasticity of a sample on a subcellular scale.Here,we describe the first application of micromechanical mapping based on Brillouin scattering spectroscopy to probe the stifness of individual amyloid plaques in the hippocampal part of the brain of a B-amyloid overexpressi ng transgenic mouse.Correlative analysis based on Brillouin and Raman microspectroscopy showed that amyloid plaques have a complex structure with a rigid core of B-pleated shoet conformation(B-aryloid)protein sur-rounded by a softer ring-shaped region richer in lipids and other protein conformations.These preliminary results give a new insight into the plaque biophysics and biomechanics,and a valuable contrast mechanism for the study and diagnosis of amnyloidopathy.展开更多
Protein misfolding neurodegenerative diseases arisethrough neurotoxicity induced by aggregation of host proteins. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, mo...Protein misfolding neurodegenerative diseases arisethrough neurotoxicity induced by aggregation of host proteins. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, motor neuron disease, tauopathies and prion diseases. Collectively, these conditions are a challenge to society because of the increasing aged population and through the real threat to human food security by animal prion diseases. It is therefore important to understand the cellular and molecular mechanisms that underlie protein misfolding--induced neurotoxicity as this will form the basis for designing strategies to alleviate their burden. Prion diseases are an important paradigm for neurodegenerative conditions in general since several of these maladies have now been shown to display prion--like phenomena. Increasingly, cell cycle activity and the DNA damage response are recognised as cellular events that participate in the neurotoxic process of various neurodegenerative diseases, and their associated animal models, which suggests they are truly involved in the pathogenic process and are not merely epiphenomena. Here we review the role of cell cycle activity and the DNA damage response in neurodegeneration associated with protein misfolding diseases, and suggest that these events contribute towards prion--induced neurotoxicity. In doing so, we highlight PrP transgenic Drosophila as a tractable model for the genetic analysis of transmissible mammalian prion disease.展开更多
文摘Two major causes of human aging include protein misfolding and free radicals. Protein misfolding occurs when proteins which are synthesized by cells do not have the proper amino acid sequence or do not achieve the correct three-dimensional configuration to function properly. Peer-reviewed scientific literature explains how these processes contribute to many age-associated diseases. A few examples include cancer, heart disease, dementias including Parkinson’s and Alzheimer’s </span><span style="font-family:Verdana;">diseases, and arthritis. This article reviews how protein misfolding can be slowed and even reversed by appropriate nutrition, potentially slowing and reversing these diseases. One cause of misfolding is mRNA translation occurring too rapidly for proper chaperone binding or protein folding. A second cause is deficiency of amino acids so improper tRNA binding occurs. A third cause is free radicals. They cause mutations promoting misfolding and cancer, and oxidize lipoproteins causing plaque in circulation promoting heart disease and stroke. Nutrients with proven actions will contribute to longer healthspans for our aging population. Healthspan is the number of healthy years before chronic or terminal diseases substantially impair the quality of life. This can be done especially by slowing and reversing these three causes of PM. Niacin, quercetin, EGCG, alpha-lipoic acid, N-acetyl-carnitine, tyrosine and cysteine address protein misfolding. Vitamin C and glutathione trap free radicals. Vitamin K amplifies free radical cancer killing by vitamin C and activates decalcification enzymes which remove calcium deposits in the circulatory system and strengthen bones. Apigenin activates the pathway of caloric restriction and induces cancer cell apoptosis. This article provides citations and explanations of the progress showing new ways to maintain health as we age. For convenience and cost savings, many of these ingredients can be consumed in supplement form, taken twice a day to maintain water-soluble nutrient levels.
文摘Klebsiella has been considered as initiator of AS(ankylosing spondylitis)for nearly four decades.This study aimed to demonstrate that Klebsiella triggers ERS(endoplasmic reticulum stress)and HLA-B27 heavy chain misfolding.CA46 cells or splenocytes obtained from wild-type,MyD88/or TLR9/mice were stimulated with KP(Klebsiella pneumoniae)or its components including CPS(capsule polysaccharide),LPS(lipopolysaccharide),and KP gDNA(genomic deoxyribonucleic acid)respectively for 24 h and 48 h.The activation of ERS-related signaling was detected by Western blotting or RT-PCR,and the level of misfolded HLA-B27 was determined by non-reducing protein gel electrophoresis and Western blotting.The protein expression of BiP/Grp78 and calreticulin,the alternative splicing of XBP-1 mRNA(messenger ribonucleic acid),and the activation of caspase-12 and p38 were increased in a dose-dependent manner in HLA-B27-expressing CA46 cells after treatment with decapsulated KP.We also demonstrate that the EP,S-inducing effects occur via the TLR(Toll-like receptor)/MyD88-dependent signaling pathway.Significantly,HLA-B27 misfolding was also detected in decapsulated KP-treated B27-expressing cells.These results suggest that the non-antigen-specific induction of ERS and B27 misfoiding through TLR/MyD88 signaling might promote KP antigen-initiated autoreactive responses via the presentation of misfolded B27,and that small-molecules targeting TLRs might have potential as novel therapeutic agents for AS.
基金supported by the National Natural Science Foundation of China,No.82160255(to RX)the Natural Science Foundation of Jiangxi Province,No.20212BAB216026(to HL)+2 种基金Science and Technology Plan Project of Health Commission of Jiangxi Province,No.202110016(to HL)Science and Technology Plan Project of Jiangxi Provincial Administration of Traditional Chinese Medicine,No.2022B975(to HL)a grant from Jiangxi Province Key Laboratory of Neurology,No.2024SSY06081(to RX).
文摘With the gradual advancement of research methods and technologies,various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases.However,current descriptions of these biological processes do not fully explain the onset,progression,and development of these conditions.Therefore,exploration of the pathogenesis of neurodegenerative diseases remains a valuable area of research.This review summarizes the potential common pathogeneses of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,Huntington’s disease,frontotemporal lobar dementia,and Lewy body disease.Research findings have indicated that several common biological processes,including aging,genetic factors,progressive neuronal dysfunction,neuronal death and apoptosis,protein misfolding and aggregation,neuroinflammation,mitochondrial dysfunction,axonal transport defects,and gut microbiota dysbiosis,are involved in the pathogenesis of these six neurodegenerative diseases.Based on current information derived from diverse areas of research,these biological processes may form complex pathogenic networks that lead to distinctive types of neuronal death in neurodegenerative diseases.Furthermore,promoting the regeneration of damaged neurons may be achievable through the repair of affected neural cells if the underlying pathogenesis can be prevented or reversed.Hence,these potential common biological processes may represent only very small,limited elements within numerous intricate pathogenic networks associated with neurodegenerative diseases.In clinical treatment,interfering with any single biological process has proven insufficient to completely halt the progression of neurodegenerative diseases.Therefore,future research on the pathogenesis of neurodegenerative diseases should focus on uncovering the complex pathogenic networks,rather than isolating individual biological processes.Based on this,therapies that aim to block or reverse various targets involved in the potential pathogenic mechanisms of neurodegenerative diseases may be promising directions,as current treatment methods that focus on halting a single pathogenic factor have not achieved satisfactory efficacy.
基金the Animal Review and Ethics Board(AREB)of the University of Saskatchewan(Animal Use Protocol#20070090).
文摘Background:Accumulatingα-synuclein(α-syn)aggregates in neurons and glial cells are the staples of many synucleinopathy disorders,such as Parkinson’s disease(PD).Since brain adenosine becomes greatly elevated in ageing brains and chronic adenosine A1 receptor(A1R)stimulation leads to neurodegeneration,we determined whether adenosine or A1R receptor ligands mimic the action of known compounds that promoteα-syn aggregation(e.g.,the amphetamine analogue 2-aminoindan)or inhibitα-syn aggregation(e.g.,Rasagiline metabolite 1-aminoindan).In the present study,we determined whether adenosine,A1R receptor agonist N^(6)-Cyclopentyladenosine(CPA)and antago-nist 8-cyclopentyl-1,3-dipropylxanthine(DPCPX)could directly interact withα-syn to modulateα-syn aggregation and neurodegeneration of dopaminergic neurons in the substantia nigra(SN).Methods:Nanopore analysis and molecular docking were used to test the binding properties of CPA and DPCPX withα-syn in vitro.Sprague-Dawley rats were administered with 7-day intraperitoneal injections of the A1R ligands and 1-and 2-aminoindan,and levels ofα-syn aggregation and neurodegeneration were examined in the SN pars compacta and hippocampal regions using confocal imaging and Western blotting.Results:Using nanopore analysis,we showed that the A1R agonists(CPA and adenosine)interacted with the N-terminus ofα-syn,similar to 2-aminoindan,which is expected to promote a“knot”conformation andα-syn misfolding.In contrast,the A1R antagonist DPCPX interacted with the N-and C-termini ofα-syn,similar to 1-aminoindan,which is expected to promote a“loop”conformation that preventsα-syn misfolding.Molecular docking studies revealed that adenosine,CPA and 2-aminoindan interacted with the hydrophobic core ofα-syn N-terminus,whereas DPCPX and 1-aminoindan showed direct binding to the N-and C-terminal hydrophobic pockets.Confocal imaging and Western blot analyses revealed that chronic treatments with CPA alone or in combination with 2-aminoindan increasedα-syn expression/aggregation and neurodegeneration in both SN pars compacta and hippocampus.In contrast,DPCPX and 1-aminoindan attenuated the CPA-inducedα-syn expression/aggregation and neurodegeneration in SN and hippocampus.Conclusions:The results indicate that A1R agonists and drugs promoting a“knot”conformation ofα-syn can causeα-synucleinopathy and increase neuronal degeneration,whereas A1R antagonists and drugs promoting a“loop”con-formation ofα-syn can be harnessed for possible neuroprotective therapies to decreaseα-synucleinopathy in PD.
文摘Protein misfolding is a general causation of classical conformational diseases and many pathogenic changes that are the result of structural conversion.Here I review recent progress in clinical and computational approaches for each stage of the misfolding process,aiming to present readers an outline for swift comprehension of this field.
基金supported by a grant from NIH(R01AI132695)to RM。
文摘Chronic wasting disease—a prion disease affecting cervids:Many neurological conditions,including Alzheimer's and Parkinson's diseases,amyotrophic lateral sclerosis,frontotemporal dementias,among others,are caused by the accumulation of misfolded proteins in the brain.These diseases affect not only humans,but also animals.
基金supported by the National Key R&D Program of China,No.2021YFA0805200(to SY)the National Natural Science Foundation of China,No.31970954(to SY)two grants from the Department of Science and Technology of Guangdong Province,Nos.2021ZT09Y007,2020B121201006(both to XJL)。
文摘Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.
基金supported by the Scientific Research Cultivation Foundation of Capital Medical University(No.PYZ2018101).
文摘Studies have demonstrated the association between black carbon(BC)particles and elevated risk of cardiovascular disease.However,the mechanisms underlying this relationship remain unclear.This study aims to investigate the effects of BC exposure on gene expressions in mice myocardium.Mice were divided into 3 groups(phosphate buffer saline(PBS)group,C50 group(50μg BC)and C100 group(100μg BC)).RNA sequencing was employed to conduct transcriptome analysis on myocardium samples.The expression levels of candidate genes were verified by qRT-PCR.Western Blot and Immunohistochemistry techniques were utilized to evaluate the expression of heat shock protein 70(Hsp70).BC exposure can cause an increase in the level of cardiac I-1βand IL-6.Transcriptome analysis revealed 1027 differentially expressed genes(DEGs)in the C100 group compared with the PBS group.Gene Ontology(GO)enrichment analysis demonstrated that these DEGs were primarily enriched in misfolded protein binding,respiratory chain and ATP metabolic process.Additionally,Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis indicated significant enrichment of DEGs in pathwaysmainly related to prion disease,oxidative phosphorylation and reactive oxygen species.HSPA1A and HSPA1B,as Hsp70 family genes,were enriched in GO term of misfolded protein binding and prion disease pathway.Moreover,the expression of cardiac Hsp70 was significantly decreased in both BC groups and showed a negative association with pro-inflammatory factors expression.BC exposure has been shown to cause inflammatory injury and may induce protein misfolding.Notably,Hsp70 was a potential cardioprotective factor and target for BC pollution-related effects.
基金supported by the National Clinical Research Center for Geriatric Diseases Foundation of Chinese PLA General Hospital(NCRCG-PLAGH-2024007).
文摘Cardiac amyloidosis(CA)is characterized by the deposition of the misfolded amyloid precursor proteins in the myocardium of the heart.The systemic form of CA is mainly caused by either the misfolded monoclonal immunoglobulin light chains(kappa and lambda)or transthyretin.[1]The clinical manifestations are mainly overlap with symptoms of other cardiovascular diseases mostly hypertrophic cardiomyopathy and heart failure.Some cases often overlooked and remains undiagnosed because of the atypical clinical manifestations,especially in the elderly.
基金This work was supported by the National Natural Science Foundation of China （No. 30470587, No. 30600197）.
文摘There are two degradation systems in mammalian cells, autophagy/lysosomal pathway and ubiquitin-proteasome pathway. Proteasome is consist of multiple protein subunits and plays important roles in degradation of short-lived cellular proteins. Recent studies reveal that proteasomal degradation system is also involved in signal transduction and regulation of various cellular functions. Dysfunction or dysregulation of proteasomal function may thus be an important pathogenic mechanism in certain neurological disorders. This paper reviews the biological functions of proteasome in signal transduction and its potential roles in neurodegenerative diseases.
基金Work at the authors’laboratories is supported by grants from"la Caixa"FoundationGrant Agreement LCF/PR/HR21/52410002+4 种基金EJP RD COFUND-EJP N°825575"Alexander"to DPS and MPAgencia Estatal de Investigacion,MICINN and ERDF Grant No.RTI2018-097624-B-I00 and PID2021-126827OB-I00 to DPSgrants from the Swedish Research Council(2017-02255)ALF Gothenburg(146051)The Swedish Society for Medical Research,Hj?rnfonden,S?derberg’s Foundations,Hagstr?mer’s Foundation Millennium,Ami?v’s Foundation,E.Jacobson’s Donation Fund,the Swedish Stroke Foundation,NanoNet COST Action(BM1002),EU FP 7 Program TargetBraln(279017)to MP。
文摘Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein,a type III intermediate filament protein expressed in astrocytes.Both early(infantile or juvenile)and adult onsets of the disease are known and,in both cases,astrocytes present characteristic aggregates,named Rosenthal fibers.Mutations are spread along the glial fibrillary acidic protein sequence disrupting the typical filament network in a dominant manner.Although the presence of aggregates suggests a proteostasis problem of the mutant forms,this behavior is also observed when the expression of wild-type glial fibrillary acidic protein is increased.Additionally,several isoforms of glial fibrillary acidic protein have been described to date,while the impact of the mutations on their expression and proportion has not been exhaustively studied.Moreover,the posttranslational modification patterns and/or the protein-protein interaction networks of the glial fibrillary acidic protein mutants may be altered,leading to functional changes that may modify the morphology,positioning,and/or the function of several organelles,in turn,impairing astrocyte normal function and subsequently affecting neurons.In particular,mitochondrial function,redox balance and susceptibility to oxidative stress may contribute to the derangement of glial fibrillary acidic protein mutant-expressing astrocytes.To study the disease and to develop putative therapeutic strategies,several experimental models have been developed,a collection that is in constant growth.The fact that most cases of Alexander disease can be related to glial fibrillary acidic protein mutations,together with the availability of new and more relevant experimental models,holds promise for the design and assay of novel therapeutic strategies.
文摘Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link between different PMDs,including Alzheimer disease(AD)and type 2 diabetes(T2D),AD and Parkinson disease(PD),and AD and prion disease.Among them,AD and T2D are the most prevalent PMDs,affecting millions of people globally,while Ab and hIAPP are the causative peptides responsible for AD and T2D,respectively.Increasing clinical and epidemiological evidences lead to a hypothesis that the cross-seeding of Ab and hIAPP is more biologically responsible for a pathological link between AD and T2D.In this review,we particularly focus on(i)the most recent and important findings of amyloid cross-seeding between Ab and hIAPP from in vitro,in vivo,and in silico studies,(ii)a mechanistic role of structural compatibility and sequence similarity of amyloid proteins(beyond Ab and hIAPP)in amyloid cross-seeding,and(iii)several current challenges and future research directions in this lessstudied field.Review of amyloid cross-seeding hopefully provides some mechanistic understanding of amyloidogenesis and inspires more efforts for the better design of next-generation drugs/strategies to treat different PMDs simultaneously.
基金University of Florence(Fondi Ateneo to RC and CC)Ministry of Education,Universities and Research of Italy(Progetto Dipartimento di Eccellenza to CC)。
文摘The misfolding and aggregation of a-synuclein is the general hallmark of a group of devastating neurodegenerative pathologies referred to as synucleinopathies,such as Parkinson’s disease,dementia with Lewy bodies,and multiple system atrophy.In such conditions,a range of different misfolded aggregates,including oligomers,protofibrils,and fibrils,are present both in neurons and glial cells.Growing expe rimental evidence supports the proposition that solu ble oligomeric assemblies,formed during the early phases of the aggregation process,are the major culprits of neuronal toxicity;at the same time,fibrillar confo rmers appear to be the most efficient at propagating among interconnected neurons,thus contributing to the spreading ofα-synuclein pathology.Moreover,α-synuclein fibrils have been recently repo rted to release soluble and highly toxic oligomeric species,responsible for an immediate dysfunction in the recipient neurons.In this review,we discuss the current knowledge about the plethora of mechanisms of cellular dysfunction caused byα-synuclein oligome rs and fibrils,both contributing to neurodegeneration in synucleinopathies.
文摘The neurodegenerative polyglutamine diseases are caused various disease proteins. Although these mutant proteins are by an expansion of unstable polyglutamine repeats in expressed ubiquitously in neuronal and non-neuronal cells, they cause selective degeneration of specific neuronal populations. Recently, increasing evidence shows that polyglutamine disease proteins also affect non-neuronal cells. However, it remains unclear how the expression of polyglutamine proteins in non-neuronal cells contributes to the course of the polyglutamine diseases. Here, we discuss recent findings about the expression of mutant polyglutamine proteins in non-neuronal cells and their influence on neurological symptoms. Understanding the contribution of non-neuronal polyglutamine proteins to disease progres- sion will help elucidate disease mechanisms and also help in the development of new treatment options.
文摘Introduction: As a chaperone, heat shock protein acts as central integrators of protein homeostasis in cell. The form of these functions is to help setting up a complex protein molecular fold (folded protein) in many important settings, such as growth, differentiation, and the ability to live. It has become clear that the control system plays an important role if the folding process fails or an error occurs, causing folding abnormalities and targeted functionality to accumulate. The accumulation of faulty protein folding would harm cells and can result in death. Apparently, there is a correlation between protein folding error with various diseases, such as diabetes mellitus and cancer. Method: We examined protein levels in all samples using Dotblott with monoclonal antibody anti-Hsp40 and anti-Hsp70. Levels of the protein content was read using a densitometer. Modification of Dot Blot was as follows: treatment was conducted with 3 × SSC, added with 20 mL blocking solution, add with total protein samples of 10 mg/ml on nitrocellulose paper, prehybridized, incubated at 70° for 30 seconds, incubated at 70° for 30 seconds with primary antibody anti-Hsp40 or Hsp70 protein and then added with second antibody HRP anti-Hsp40 or Hsp70 protein, treated with 3 × SSC and visualized with TSA HRP, and then administered with streptavidin, biothynil tyramide, and, finally, added with chromogen (DAB) in a confined space. Result: From the analysis of the data using Manova test with Wilk’s Lambda, there were significant differences in the levels of Hsp40 between Benign Oral Lesion (mean 688.31 area) and OSCC (mean 1354.59 area) patients (p 0.070), there was also a highly significant difference in Hsp70 levels between patients who experienced Benign Oral Lesion (mean 529.82 area) and OSCC (mean 1346.32 area) patients (p 0.006). Conclusion: OSCC patients have increased Hsp70 levels, so it is possible that something is going wrong in protein folding. Errors in protein folding result in a new homeostasis or inhibition of apoptosis and increasing cell proliferation that triggers carcinogenesis. Hsp40 acts as co-chaperones.
文摘Protein quality control involves many processes that jointly act to regulate the expression, localization, turnover, and degradation of proteins, and has been highlighted in recent studies as critical to the differentiation of stem cells during regeneration. The roles of constitutively secreted extracellular chaperones in neuronal injury and disease are poorly understood. Extracellular chaperones are multifunctional proteins expressed by many cell types, including those of the nervous system, known to facilitate protein quality control processes. These molecules exert pleiotropic effects and have been implicated as playing important protective roles in a variety of stress conditions, including tissue damage, infections, and local tissue inflammation. This article aims to provide a critical review of what is currently known about the functions of extracellular chaperones in neuronal repair and regeneration and highlight future directions for this important research area. We review what is known of four constitutively secreted extracellular chaperones directly implicated in processes of neuronal damage and repair, including transthyretin, clusterin, α2-macroglobulin, and neuroserpin, and propose that investigation into the effects of these and other extracellular chaperones on neuronal repair and regeneration has the potential to yield valuable new therapies.
基金supported by the National Natural Science Foundation of China,Nos.30560042,81160161,81360198,82160255a grant from Department of Education of Jiangxi Province,Nos.GJJ13198,GJJ170021+1 种基金Jiangxi Provincial Department of Science and Technology,Nos.[2014]-47,20142BBG70062,20171BAB215022,20192BAB205043Science and Technology Plan of Jiangxi Commission of Health,Nos.202210002,202310119(all to RX).
文摘Amyotrophic lateral sclerosis is a neurodegenerative disease,and the molecular mechanism underlying its pathology remains poorly understood.However,inflammation is known to play an important role in the development of this condition.To identify driver genes that affect the inflammatory response in amyotrophic lateral sclerosis,as well as potential treatment targets,it is crucial to analyze brain tissue samples from patients with both sporadic amyotrophic lateral sclerosis and C9orf72-related amyotrophic lateral sclerosis.Therefore,in this study we used a network-driven gene analysis tool,NetBID2.0,which is based on SJARACNe,a scalable algorithm for the reconstruction of accurate cellular networks,to experimentally analyze sequencing data from patients with sporadic amyotrophic lateral sclerosis.The results showed that the OSMR gene is pathogenic in amyotrophic lateral sclerosis and participates in the progression of amyotrophic lateral sclerosis by mediating the neuroinflammatory response.Furthermore,there were differences in OSMR activity and expression between patients with sporadic amyotrophic lateral sclerosis and those with C9orf72-related amyotrophic lateral sclerosis.These findings suggest that OSMR may be a diagnostic and prognostic marker for amyotrophic lateral sclerosis.
基金Project supported by the National Natural Science Foundation of China (Grant Nos.52073128,12164002,and 11964012)the Foundation of Educational Committee of Jiangxi Province of China (Grant No.GJJ211112)the Fund for Distinguished Young Scholars of Jiangxi Science&Technology Normal University (Grant No.2015QNBJRC002)。
文摘Prion diseases are a class of fatal neurodegenerative diseases caused by misfolded prion proteins.The main reason is that pathogenic prion protein has a strong tendency to aggregate,which easily induces the damage to the central nervous system.Point mutations in the human prion protein gene can cause prion diseases such as Creutzfeldt-Jakob and Gerstmann's syndrome.To understand the mechanism of mutation-induced prion protein aggregation,the mutants in an aqueous solution are studied by molecular dynamics simulations,including the wild type,V180I,H187R and a double point mutation which is associated with CJD and GSS.After running simulations for 500 ns,the results show that these three mutations have different effects on the kinetic properties of PrP.The high fluctuations around the N-terminal residues of helix 2 in the V180I variant lead to a decrease in hydrogen bonding on helix 2,while an increase in the number of hydrogen bonds between the folded regions promotes the generation ofβ-sheet.Meanwhile,partial deletion of salt bridges in the H187R and double mutants allows the sub-structural domains of the prion protein to separate,which would accelerate the conversion from PrPC to PrPSc.A similar trend is observed in both SASA and Rg for all three mutations,indicating that the conformational space is reduced and the structure is compact.
基金supported by the Wellcome Trust Institutional Strategic Support Award (WT105618MA)supported by the Engineering and Physical Sciences Research Council (EP/M028739/1).
文摘A myloidopathy is one of the most prominent hallmarks of Alkheimer's disease(AD),the leading cause of dementia worldwide,and is characterized by the accumulation of amyloid plaques in the brain parenchyma.The plaques consist of abnornal deposits mainly composed of an aggregation-prone protein fragment,B-amyloid 140/1-42,into the extracellular matrix.Brillouin micro-spectroscopy is an all-optical contactless technique that is based on the interaction between visible light and longitudinal acoustic waves or phonons,giving access to the viscoelasticity of a sample on a subcellular scale.Here,we describe the first application of micromechanical mapping based on Brillouin scattering spectroscopy to probe the stifness of individual amyloid plaques in the hippocampal part of the brain of a B-amyloid overexpressi ng transgenic mouse.Correlative analysis based on Brillouin and Raman microspectroscopy showed that amyloid plaques have a complex structure with a rigid core of B-pleated shoet conformation(B-aryloid)protein sur-rounded by a softer ring-shaped region richer in lipids and other protein conformations.These preliminary results give a new insight into the plaque biophysics and biomechanics,and a valuable contrast mechanism for the study and diagnosis of amnyloidopathy.
文摘Protein misfolding neurodegenerative diseases arisethrough neurotoxicity induced by aggregation of host proteins. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, motor neuron disease, tauopathies and prion diseases. Collectively, these conditions are a challenge to society because of the increasing aged population and through the real threat to human food security by animal prion diseases. It is therefore important to understand the cellular and molecular mechanisms that underlie protein misfolding--induced neurotoxicity as this will form the basis for designing strategies to alleviate their burden. Prion diseases are an important paradigm for neurodegenerative conditions in general since several of these maladies have now been shown to display prion--like phenomena. Increasingly, cell cycle activity and the DNA damage response are recognised as cellular events that participate in the neurotoxic process of various neurodegenerative diseases, and their associated animal models, which suggests they are truly involved in the pathogenic process and are not merely epiphenomena. Here we review the role of cell cycle activity and the DNA damage response in neurodegeneration associated with protein misfolding diseases, and suggest that these events contribute towards prion--induced neurotoxicity. In doing so, we highlight PrP transgenic Drosophila as a tractable model for the genetic analysis of transmissible mammalian prion disease.
