Currently,our understanding of the pathogenesis of major neurodegenerative disorders,such as Alzheimer's,Parkinson's,and Huntington's diseases,is largely shaped by the amyloid cascade hypothesis.Pa rticula...Currently,our understanding of the pathogenesis of major neurodegenerative disorders,such as Alzheimer's,Parkinson's,and Huntington's diseases,is largely shaped by the amyloid cascade hypothesis.Pa rticularly,this hypothesis posits that in Alzheimer's disease,the aggregation of amyloid-beta peptide initiates a series of pathological processes leading to neuronal dysfunction and death(Zhang et al.,2024).展开更多
Chemical exchange saturation transfer magnetic resonance imaging is an advanced imaging technique that enables the detection of compounds at low concentrations with high sensitivity and spatial resolution and has been...Chemical exchange saturation transfer magnetic resonance imaging is an advanced imaging technique that enables the detection of compounds at low concentrations with high sensitivity and spatial resolution and has been extensively studied for diagnosing malignancy and stroke.In recent years,the emerging exploration of chemical exchange saturation transfer magnetic resonance imaging for detecting pathological changes in neurodegenerative diseases has opened up new possibilities for early detection and repetitive scans without ionizing radiation.This review serves as an overview of chemical exchange saturation transfer magnetic resonance imaging with detailed information on contrast mechanisms and processing methods and summarizes recent developments in both clinical and preclinical studies of chemical exchange saturation transfer magnetic resonance imaging for Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and Huntington’s disease.A comprehensive literature search was conducted using databases such as PubMed and Google Scholar,focusing on peer-reviewed articles from the past 15 years relevant to clinical and preclinical applications.The findings suggest that chemical exchange saturation transfer magnetic resonance imaging has the potential to detect molecular changes and altered metabolism,which may aid in early diagnosis and assessment of the severity of neurodegenerative diseases.Although promising results have been observed in selected clinical and preclinical trials,further validations are needed to evaluate their clinical value.When combined with other imaging modalities and advanced analytical methods,chemical exchange saturation transfer magnetic resonance imaging shows potential as an in vivo biomarker,enhancing the understanding of neuropathological mechanisms in neurodegenerative diseases.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
The exchange of information and materials between organelles plays a crucial role in regulating cellular physiological functions and metabolic levels.Mitochondria-associated endoplasmic reticulum membranes serve as ph...The exchange of information and materials between organelles plays a crucial role in regulating cellular physiological functions and metabolic levels.Mitochondria-associated endoplasmic reticulum membranes serve as physical contact channels between the endoplasmic reticulum membrane and the mitochondrial outer membrane,formed by various proteins and protein complexes.This microstructural domain mediates several specialized functions,including calcium(Ca^(2+))signaling,autophagy,mitochondrial morphology,oxidative stress response,and apoptosis.Notably,the dysregulation of Ca^(2+)signaling mediated by mitochondria-associated endoplasmic reticulum membranes is a critical factor in the pathogenesis of neurological diseases.Certain proteins or protein complexes within these membranes directly or indirectly regulate the distance between the endoplasmic reticulum and mitochondria,as well as the transduction of Ca^(2+)signaling.Conversely,Ca^(2+)signaling mediated by mitochondria-associated endoplasmic reticulum membranes influences other mitochondria-associated endoplasmic reticulum membraneassociated functions.These functions can vary significantly across different neurological diseases—such as ischemic stroke,traumatic brain injury,Alzheimer's disease,Parkinson's disease,amyotrophic lateral sclerosis,and Huntington's disease—and their respective stages of progression.Targeted modulation of these disease-related pathways and functional proteins can enhance neurological function and promote the regeneration and repair of damaged neurons.Therefore,mitochondria-associated endoplasmic reticulum membranes-mediated Ca^(2+)signaling plays a pivotal role in the pathological progression of neurological diseases and represents a significant potential therapeutic target.This review focuses on the effects of protein complexes in mitochondria-associated endoplasmic reticulum membranes and the distinct roles of mitochondria-associated endoplasmic reticulum membranes-mediated Ca^(2+)signaling in neurological diseases,specifically highlighting the early protective effects and neuronal damage that can result from prolonged mitochondrial Ca^(2+)overload or deficiency.This article provides a comprehensive analysis of the various mechanisms of Ca^(2+)signaling mediated by mitochondria-associated endoplasmic reticulum membranes in neurological diseases,contributing to the exploration of potential therapeutic targets for promoting neuroprotection and nerve repair.展开更多
In 1872, George Huntington presented his essay “On Chorea” to the Meigs and Mason Academy of Medicine and, in doing so, detailed a disease that would later bear his name. Huntington's disease(HD) is a genetic, n...In 1872, George Huntington presented his essay “On Chorea” to the Meigs and Mason Academy of Medicine and, in doing so, detailed a disease that would later bear his name. Huntington's disease(HD) is a genetic, neurodegenerative disease that manifests as the loss of motor control,cognitive impairment,and mood and psychiatric changes in paents.展开更多
Background:The prevalence,age of onset,and symptomatology of traumatic brain injury,stroke,and neurodegenerative diseases(such as Alzheimer’s disease(AD),Parkinson’s disease,amyotrophic lateral sclerosis,and Hunting...Background:The prevalence,age of onset,and symptomatology of traumatic brain injury,stroke,and neurodegenerative diseases(such as Alzheimer’s disease(AD),Parkinson’s disease,amyotrophic lateral sclerosis,and Huntington’s disease)differ substantially between males and females.The higher prevalence of these brain disorders has been attributed to females having a greater longevity compared with males.Since one of the greatest risk factors of acquired brain injury(such as stroke,traumatic brain injury caused by fall)and neurodegenerative disease is age.展开更多
Huntington’s disease(HD)is a genetic disease characterized by the progressive degeneration of the striatum and cortex.Patients can present with a variety of symptoms that can broadly be classified into motor symptoms...Huntington’s disease(HD)is a genetic disease characterized by the progressive degeneration of the striatum and cortex.Patients can present with a variety of symptoms that can broadly be classified into motor symptoms,inclusive of choreatic movements and rigidity,mood and psychiatric symptoms,such as depression and apathy,and cognitive symptoms,such as cognitive decline.The causal mutation underlying HD results from an expansion of a CAG repeat sequence on the IT15 gene,resulting in the formation and accumulation of a mutant huntingtin protein.展开更多
Brain-derived neurotrophic factor(BDNF)exerts pleiotropic effects on brain processes including psychiatric disorders,aging,neurodegeneration,and metabolic homeostasis.A simple PubMed search using the key word“BDNF,”...Brain-derived neurotrophic factor(BDNF)exerts pleiotropic effects on brain processes including psychiatric disorders,aging,neurodegeneration,and metabolic homeostasis.A simple PubMed search using the key word“BDNF,”to date,yields over 33,000 publications.From fundamental biology to potential therapeutic applications,BDNF has clearly garnered extensive and significant attention in the field of neurobiology research.展开更多
TDP-43 proteinopathies and cryptic exons:Transactive response DNA binding protein of 43 kDa(TDP-43)is a ubiquitously expressed RNA/DNA binding protein crucial for coding and non-coding RNA metabolism including transcr...TDP-43 proteinopathies and cryptic exons:Transactive response DNA binding protein of 43 kDa(TDP-43)is a ubiquitously expressed RNA/DNA binding protein crucial for coding and non-coding RNA metabolism including transcription,splicing,transport,translation,and turnover.TDP-43 shuttles between the nucleus and cytoplasm,but is predominantly localized in the nucleus.Neurodegenerative diseases(NDs)may be accompanied by nuclear loss and possible cytoplasmic accumulation and aggregation of TDP-43 in vulnerable neurons and beyond.This neuropathology is the hallmark of most individuals suffering from amyotrophic lateral sclerosis(ALS),frontotemporal dementia(FTD)with TDP-43-immunoreactive pathology(FTD-TDP),limbic-predominant age-related TDP-43 encephalopathy(LATE)and Perry syndrome,but also coexists with the primary pathology in subsets of patients suffering from other NDs,such as Alzheimer’s disease,Lewy body dementias,or Huntington’s disease.Variants in the gene encoding TDP-43(TARDBP)are the cause of ALS and/or FTD in some rare cases substantiating the importance of this protein in aging neurons.It is still controversial if loss of nuclear,or increased cytoplasmic and/or aggregating TDP-43 is more harmful to neurons(Nag and Schneider,2023).Recently,the role of nuclear TDP-43 in repressing the inclusion of intronic sequences,named cryptic exons(CEs),into mature mRNAs gained much attention.展开更多
Objective To make early diagnosis of IT15 gene mutation in a Wuhan juvenile-onset Huntington disease （HD） family, for providing them with genetic counseling, and making preparation for the further research on pathog...Objective To make early diagnosis of IT15 gene mutation in a Wuhan juvenile-onset Huntington disease （HD） family, for providing them with genetic counseling, and making preparation for the further research on pathogenesis and experimental therapy of HD. Methods According to the principle of informed consent, we extracted genomic DNA from peripheral blood samples and carried genetic diagnosis of pathogenic exon 1 of IT15 gene by modified touchdown PCR and DNA sequencing methods. Results Eight of twenty-five family members carried abnormal allele： Ⅲ10 Ⅲ12, IIIt4, Ⅳ3, and Ⅴ2 carded （CAG） 48, Ⅳ11 and Ⅳ12 carried （CAG） 67, and Ⅳ14 carried （CAG） 63, in contrast with the 8-25 CAG trinucleotides in the members of control group. Ⅳ14 carried 15 more CAG trinucleotides than her father Ⅲ10. Conclusion The results definitely confirm the diagnosis of HD and indicate the CAG trinucleotide repeat expansion of IT15 gene in this HD family. In addition, CAG expansion results in juvenile-onset and anticipation （characterized by earlier age of onset and increasing severity） of the patientⅣ12.展开更多
神经退行性疾病（degenerative diseases of the central nervous system,ND）是一组以原发性神经元变性为基础的慢性进行性神经系统疾病。该类疾病主要包括阿尔茨海默氏病（Alzheimer＇s disease,AD）、帕金森病（Parkinson＇s disease...神经退行性疾病（degenerative diseases of the central nervous system,ND）是一组以原发性神经元变性为基础的慢性进行性神经系统疾病。该类疾病主要包括阿尔茨海默氏病（Alzheimer＇s disease,AD）、帕金森病（Parkinson＇s disease,PD）、Huntington舞蹈病（huntington disease,HD）、脑缺血缺氧所致神经元变性等。展开更多
基金funded by the Russian Science Foundation(grant No.23-74-10092)(to AIS)。
文摘Currently,our understanding of the pathogenesis of major neurodegenerative disorders,such as Alzheimer's,Parkinson's,and Huntington's diseases,is largely shaped by the amyloid cascade hypothesis.Pa rticularly,this hypothesis posits that in Alzheimer's disease,the aggregation of amyloid-beta peptide initiates a series of pathological processes leading to neuronal dysfunction and death(Zhang et al.,2024).
基金supported by The University of Hong Kong,China(109000487,109001694,204610401,and 204610519)National Natural Science Foundation of China(82402225)(to JH).
文摘Chemical exchange saturation transfer magnetic resonance imaging is an advanced imaging technique that enables the detection of compounds at low concentrations with high sensitivity and spatial resolution and has been extensively studied for diagnosing malignancy and stroke.In recent years,the emerging exploration of chemical exchange saturation transfer magnetic resonance imaging for detecting pathological changes in neurodegenerative diseases has opened up new possibilities for early detection and repetitive scans without ionizing radiation.This review serves as an overview of chemical exchange saturation transfer magnetic resonance imaging with detailed information on contrast mechanisms and processing methods and summarizes recent developments in both clinical and preclinical studies of chemical exchange saturation transfer magnetic resonance imaging for Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and Huntington’s disease.A comprehensive literature search was conducted using databases such as PubMed and Google Scholar,focusing on peer-reviewed articles from the past 15 years relevant to clinical and preclinical applications.The findings suggest that chemical exchange saturation transfer magnetic resonance imaging has the potential to detect molecular changes and altered metabolism,which may aid in early diagnosis and assessment of the severity of neurodegenerative diseases.Although promising results have been observed in selected clinical and preclinical trials,further validations are needed to evaluate their clinical value.When combined with other imaging modalities and advanced analytical methods,chemical exchange saturation transfer magnetic resonance imaging shows potential as an in vivo biomarker,enhancing the understanding of neuropathological mechanisms in neurodegenerative diseases.
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supported by Yunnan Province Innovation Team of Prevention and Treatment for Brain Disease with Acupuncture and Tuina,No.202405AS350007Youth Top Talent Project of 10-thousand Talent Plan in Yunnan Province,No.YNWR-QNBJ-2018-345+3 种基金the National Natural Science Foundation of China,No.81960731Joint Special Project of Traditional Chinese Medicine in Science and Technology Department of Yunnan Province,Nos.2019FF002[-008],202001AZ070001-002 and 202001AZ070001-030Yunnan Province University Innovation Team Projects No.2019YGC04Yunnan Province Project Education Fund,Nos.2024Y406,2024Y414(all to PZ)。
文摘The exchange of information and materials between organelles plays a crucial role in regulating cellular physiological functions and metabolic levels.Mitochondria-associated endoplasmic reticulum membranes serve as physical contact channels between the endoplasmic reticulum membrane and the mitochondrial outer membrane,formed by various proteins and protein complexes.This microstructural domain mediates several specialized functions,including calcium(Ca^(2+))signaling,autophagy,mitochondrial morphology,oxidative stress response,and apoptosis.Notably,the dysregulation of Ca^(2+)signaling mediated by mitochondria-associated endoplasmic reticulum membranes is a critical factor in the pathogenesis of neurological diseases.Certain proteins or protein complexes within these membranes directly or indirectly regulate the distance between the endoplasmic reticulum and mitochondria,as well as the transduction of Ca^(2+)signaling.Conversely,Ca^(2+)signaling mediated by mitochondria-associated endoplasmic reticulum membranes influences other mitochondria-associated endoplasmic reticulum membraneassociated functions.These functions can vary significantly across different neurological diseases—such as ischemic stroke,traumatic brain injury,Alzheimer's disease,Parkinson's disease,amyotrophic lateral sclerosis,and Huntington's disease—and their respective stages of progression.Targeted modulation of these disease-related pathways and functional proteins can enhance neurological function and promote the regeneration and repair of damaged neurons.Therefore,mitochondria-associated endoplasmic reticulum membranes-mediated Ca^(2+)signaling plays a pivotal role in the pathological progression of neurological diseases and represents a significant potential therapeutic target.This review focuses on the effects of protein complexes in mitochondria-associated endoplasmic reticulum membranes and the distinct roles of mitochondria-associated endoplasmic reticulum membranes-mediated Ca^(2+)signaling in neurological diseases,specifically highlighting the early protective effects and neuronal damage that can result from prolonged mitochondrial Ca^(2+)overload or deficiency.This article provides a comprehensive analysis of the various mechanisms of Ca^(2+)signaling mediated by mitochondria-associated endoplasmic reticulum membranes in neurological diseases,contributing to the exploration of potential therapeutic targets for promoting neuroprotection and nerve repair.
文摘In 1872, George Huntington presented his essay “On Chorea” to the Meigs and Mason Academy of Medicine and, in doing so, detailed a disease that would later bear his name. Huntington's disease(HD) is a genetic, neurodegenerative disease that manifests as the loss of motor control,cognitive impairment,and mood and psychiatric changes in paents.
基金supported by NIH/NICHD RO1HD109157supported by his American Heart AssociationAward Career Development Award (932980)National Science Foundation CAREER award (NSF2401215)
文摘Background:The prevalence,age of onset,and symptomatology of traumatic brain injury,stroke,and neurodegenerative diseases(such as Alzheimer’s disease(AD),Parkinson’s disease,amyotrophic lateral sclerosis,and Huntington’s disease)differ substantially between males and females.The higher prevalence of these brain disorders has been attributed to females having a greater longevity compared with males.Since one of the greatest risk factors of acquired brain injury(such as stroke,traumatic brain injury caused by fall)and neurodegenerative disease is age.
文摘Huntington’s disease(HD)is a genetic disease characterized by the progressive degeneration of the striatum and cortex.Patients can present with a variety of symptoms that can broadly be classified into motor symptoms,inclusive of choreatic movements and rigidity,mood and psychiatric symptoms,such as depression and apathy,and cognitive symptoms,such as cognitive decline.The causal mutation underlying HD results from an expansion of a CAG repeat sequence on the IT15 gene,resulting in the formation and accumulation of a mutant huntingtin protein.
文摘Brain-derived neurotrophic factor(BDNF)exerts pleiotropic effects on brain processes including psychiatric disorders,aging,neurodegeneration,and metabolic homeostasis.A simple PubMed search using the key word“BDNF,”to date,yields over 33,000 publications.From fundamental biology to potential therapeutic applications,BDNF has clearly garnered extensive and significant attention in the field of neurobiology research.
基金supported by the Deutsche Forschungsgemeinschaft(DFGgrant#521487152)(to AF)。
文摘TDP-43 proteinopathies and cryptic exons:Transactive response DNA binding protein of 43 kDa(TDP-43)is a ubiquitously expressed RNA/DNA binding protein crucial for coding and non-coding RNA metabolism including transcription,splicing,transport,translation,and turnover.TDP-43 shuttles between the nucleus and cytoplasm,but is predominantly localized in the nucleus.Neurodegenerative diseases(NDs)may be accompanied by nuclear loss and possible cytoplasmic accumulation and aggregation of TDP-43 in vulnerable neurons and beyond.This neuropathology is the hallmark of most individuals suffering from amyotrophic lateral sclerosis(ALS),frontotemporal dementia(FTD)with TDP-43-immunoreactive pathology(FTD-TDP),limbic-predominant age-related TDP-43 encephalopathy(LATE)and Perry syndrome,but also coexists with the primary pathology in subsets of patients suffering from other NDs,such as Alzheimer’s disease,Lewy body dementias,or Huntington’s disease.Variants in the gene encoding TDP-43(TARDBP)are the cause of ALS and/or FTD in some rare cases substantiating the importance of this protein in aging neurons.It is still controversial if loss of nuclear,or increased cytoplasmic and/or aggregating TDP-43 is more harmful to neurons(Nag and Schneider,2023).Recently,the role of nuclear TDP-43 in repressing the inclusion of intronic sequences,named cryptic exons(CEs),into mature mRNAs gained much attention.
文摘Objective To make early diagnosis of IT15 gene mutation in a Wuhan juvenile-onset Huntington disease （HD） family, for providing them with genetic counseling, and making preparation for the further research on pathogenesis and experimental therapy of HD. Methods According to the principle of informed consent, we extracted genomic DNA from peripheral blood samples and carried genetic diagnosis of pathogenic exon 1 of IT15 gene by modified touchdown PCR and DNA sequencing methods. Results Eight of twenty-five family members carried abnormal allele： Ⅲ10 Ⅲ12, IIIt4, Ⅳ3, and Ⅴ2 carded （CAG） 48, Ⅳ11 and Ⅳ12 carried （CAG） 67, and Ⅳ14 carried （CAG） 63, in contrast with the 8-25 CAG trinucleotides in the members of control group. Ⅳ14 carried 15 more CAG trinucleotides than her father Ⅲ10. Conclusion The results definitely confirm the diagnosis of HD and indicate the CAG trinucleotide repeat expansion of IT15 gene in this HD family. In addition, CAG expansion results in juvenile-onset and anticipation （characterized by earlier age of onset and increasing severity） of the patientⅣ12.
文摘神经退行性疾病（degenerative diseases of the central nervous system,ND）是一组以原发性神经元变性为基础的慢性进行性神经系统疾病。该类疾病主要包括阿尔茨海默氏病（Alzheimer＇s disease,AD）、帕金森病（Parkinson＇s disease,PD）、Huntington舞蹈病（huntington disease,HD）、脑缺血缺氧所致神经元变性等。
