Background Despite increasing in vitro research,direct evidence of how abnormalα-synuclein(α-Syn)dysregulates vesicular transport and synaptic function in the human brain is lacking.Methods We performed a transcript...Background Despite increasing in vitro research,direct evidence of how abnormalα-synuclein(α-Syn)dysregulates vesicular transport and synaptic function in the human brain is lacking.Methods We performed a transcriptome analysis using brain tissues from a multiple system atrophy(MSA)mouse model,which develops humanα-Syn-positive glial cytoplasmic inclusion-like structures and neuronal cytoplasmic inclusion-like structures after tamoxifen injection.We then performed histologic and biochemical analyses using brain samples from 71 human cases(Parkinson’s disease,n=10;dementia with Lewy bodies[DLB],n=19;MSA,n=15;control:n=27),a human blood sample(control:n=1),and cultured cells.Results Based on the transcriptome of the MSA mouse model,we identified 10 vesicular transport proteins,including synaptotagmin 13(SYT13),that might interact withα-Syn.Immunohistochemistry using human brain samples demonstrated that of the 10 vesicular transport proteins identified in the transcriptome analysis,only SYT13 was incorporated into both Lewy bodies and glial cytoplasmic inclusions.Proximity ligation assays revealed that SYT13 exhibited a higher degree of interactions with phosphorylatedα-Syn than with endogenousα-Syn.Immunoprecipitation confirmed that SYT13 bound predominantly to phosphorylatedα-Syn,SYT1,and the soluble N-ethylmaleimide-sensitive attachment protein receptor(SNARE)complexes.Filter trap assays revealed interactions between SYT13 and soluble toxicβ-sheet-richα-Syn oligomers.Furthermore,fraction analysis showed a significant increase of SYT13 protein levels at the synapses in DLB and MSA.Notably,a correlation was observed between the levels of SYT13 and aggregatedα-Syn at the synapses.SYT13 was observed to regulate extracellular vesicle release in association with SYT1 and the SNARE complexes in SH-SY5Y cells.SYT13 overexpression in SH-SY5Y cells impaired extracellular vesicle release.Consistently,the numbers of extracellular vesicles were significantly reduced in the brain homogenates of DLB and MSA cases compared with those in controls.Conclusions Abnormalα-Syn impairs extracellular vesicle release through interactions with SYT13 in synucleinopathies.Our findings provide insights into therapeutic strategies for alleviating dysregulations of vesicular transport and synaptic function in patients with synucleinopathies.展开更多
The discovery of diagnostic and prognostic biomarkers for neurodegenerative diseases represents an unmet clinical challenge. For example, the diagnosis of Parkinson's disease (PD) relies mainly on the presence of ...The discovery of diagnostic and prognostic biomarkers for neurodegenerative diseases represents an unmet clinical challenge. For example, the diagnosis of Parkinson's disease (PD) relies mainly on the presence of clinical symptoms. Therefore, the identification and use of novel PD biomarkers would allow the application of disease-modifying treatments at the very early stages of neurodegeneration. The presynaptic protein, α-synuclein, has been genetically and biochemically linked with PD pathogenesis and has been considered as a potential biomarker for the diagnosis of PD and the related synucleinopathies. The vast majority of studies have assessed the measurement of α-synuclein, alone or in combination with other biomarkers in the cerebrospinal fluid (CSF), since it is the biofluid that most closely reflects the pathophysiology of the brain. The diagnostic value of the monomericα-synuclein but also the oligomeric, the phosphorylated and the aggregated forms of the protein has been evaluated using a variety of immunoassays. The results have so far been reproducible but the assays used are still lacking the required diagnostic accuracy. Recent reports have shown that Protein misfolding cyclic amplification is a technique that has the potential to detect α-synuclein seeds in samples of CSF with high sensitivity and across different synucleinopathies. In an effort to increase the source of biomarker for PD and related synucleinopathies,α-synuclein has also been measured in neuronal exosomes, small vesicles of endosomal origin that are secreted from neurons into the CSF or the periphery. The potential diagnostic value of exosomes stems from the notion that exosomes carry a disease-specific repertoire of marker proteins. Therefore, the assessment of exosome-associated α-synuclein species may also open up new avenues for disease diagnosis in different synucleinopathies.展开更多
Proteinopathy,defined as the abnormal accumulation of proteins that eventually leads to cell death,is one of the most significant pathological features of neurodegenerative diseases.Tauopathies,represented by Alzheime...Proteinopathy,defined as the abnormal accumulation of proteins that eventually leads to cell death,is one of the most significant pathological features of neurodegenerative diseases.Tauopathies,represented by Alzheimer’s disease(AD),and synucleinopathies,represented by Parkinson’s disease(PD),show similarities in multiple aspects.AD manifests extrapyramidal symptoms while dementia is also a major sign of advanced PD.We and other researchers have sequentially shown the cross-seeding phenomenon ofα-synuclein(α-syn)and tau,reinforcing pathologies between synucleinopathies and tauopathies.The highly overlapping clinical and pathological features imply shared pathogenic mechanisms between the two groups of disease.The diagnostic and therapeutic strategies seemingly appropriate for one distinct neurodegenerative disease may also apply to a broader spectrum.Therefore,a clear understanding of the overlaps and divergences between tauopathy and synucleinopathy is critical for unraveling the nature of the complicated associations among neurodegenerative diseases.In this review,we discuss the shared and diverse characteristics of tauopathies and synucleinopathies from aspects of genetic causes,clinical manifestations,pathological progression and potential common therapeutic approaches targeting the pathology,in the aim to provide a timely update for setting the scheme of disease classification and provide novel insights into the therapeutic development for neurodegenerative diseases.展开更多
Idiopathic rapid eye movement sleep behavior disorder(iRBD) is often a precursor to neurodegenerative disease. However, voxel-based morphological studies evaluating structural abnormalities in the brains of iRBD patie...Idiopathic rapid eye movement sleep behavior disorder(iRBD) is often a precursor to neurodegenerative disease. However, voxel-based morphological studies evaluating structural abnormalities in the brains of iRBD patients are relatively rare. This study aimed to explore cerebral structural alterations using magnetic resonance imaging and to determine their association with clinical parameters in iRBD patients. Brain structural T1-weighted MRI scans were acquired from 19 polysomnogram-confirmed iRBD patients(male:female 16:3; mean age 66.6 ± 7.0 years) and 20 age-matched healthy controls(male:female 5:15; mean age 63.7 ± 5.9 years). Gray matter volume(GMV) data were analyzed based on Statistical Parametric Mapping 8, using a voxel-based morphometry method and two-sample t-test and multiple regression analysis. Compared with controls, iRBD patients had increased GMV in the middle temporal gyrus and cerebellar posterior lobe, but decreased GMV in the Rolandic operculum, postcentral gyrus, insular lobe, cingulate gyrus, precuneus, rectus gyrus, and superior frontal gyrus. iRBD duration was positively correlated with GMV in the precuneus, cuneus, superior parietal gyrus, postcentral gyrus, posterior cingulate gyrus, hippocampus, lingual gyrus, middle occipital gyrus, middle temporal gyrus, and cerebellum posterior lobe. Furthermore, phasic chin electromyographic activity was positively correlated with GMV in the hippocampus, precuneus, fusiform gyrus, precentral gyrus, superior frontal gyrus, cuneus, inferior parietal lobule, angular gyrus, superior parietal gyrus, paracentral lobule, and cerebellar posterior lobe. There were no significant negative correlations of brain GMV with disease duration or electromyographic activity in iRBD patients. These findings expand the spectrum of known gray matter modifications in iRBD patients and provide evidence of a correlation between brain dysfunction and clinical manifestations in such patients. The protocol was approved by the Ethics Committee of Huashan Hospital(approval No. KY2013-336) on January 6, 2014. This trial was registered in the ISRCTN registry(ISRCTN18238599).展开更多
Astrocytes are integral components of the central nervous system,where they are involved in numerous functions critical for neuronal development and functioning,including maintenance of blood-brain barrier,formation o...Astrocytes are integral components of the central nervous system,where they are involved in numerous functions critical for neuronal development and functioning,including maintenance of blood-brain barrier,formation of synapses,supporting neurons with nutrients and trophic factors,and protecting them from injury.These roles are markedly affected in the course of chronic neurodegenerative disorders,often before the onset of the disease.In this review,we summarize the recent findings supporting the hypothesis that astrocytes play a fundamental role in the processes contributing to neurodegeneration.We focus onα-synucleinopathies and tauopathies as the most common neurodegenerative diseases.The mechanisms implicated in the development and progression of these disorders appear not to be exclusively neuronal,but are often related to the astrocytic-neuronal integrity and the response of astrocytes to the altered microglial function.A profound understanding of the multifaceted functions of astrocytes and identification of their communication pathways with neurons and microglia in health and in the disease is of critical significance for the development of novel mechanism-based therapies against neurodegenerative disorders.展开更多
α-Synuclein is a protein that mainly exists in the presynaptic terminals.Abnormal folding and accumulation of α-synuclein are found in several neurodegenerative diseases,including Parkinson’s disease.Aggregated and...α-Synuclein is a protein that mainly exists in the presynaptic terminals.Abnormal folding and accumulation of α-synuclein are found in several neurodegenerative diseases,including Parkinson’s disease.Aggregated and highly phospho rylated a-synuclein constitutes the main component of Lewy bodies in the brain,the pathological hallmark of Parkinson s disease.For decades,much attention has been focused on the accumulation of α-synuclein in the brain parenchyma rather than considering Parkinson s disease as a systemic disease.Recent evidence demonstrates that,at least in some patients,the initial α-synuclein pathology originates in the peripheral organs and spreads to the brain.Injection of α-synuclein preformed fibrils into the gastrointestinal tra ct trigge rs the gutto-brain propagation of α-synuclein pathology.However,whether α-synuclein pathology can occur spontaneously in peripheral organs independent of exogenous α-synuclein preformed fibrils or pathological α-synuclein leakage from the central nervous system remains under investigation.In this review,we aimed to summarize the role of peripheral α-synuclein pathology in the pathogenesis of Parkinson’s disease.We also discuss the pathways by which α-synuclein pathology spreads from the body to the brain.展开更多
Trehalose,a unique nonreducing crystalline disaccharide,is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging,intrinsic mutations,or ...Trehalose,a unique nonreducing crystalline disaccharide,is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging,intrinsic mutations,or autophagy dysregulation.This systematic review summarizes the effects of trehalose on its underlying mechanisms in animal models of selected neurodegenerative disorders(tau pathology,synucleinopathy,polyglutamine tract,and motor neuron diseases).All animal studies on neurodegenerative diseases treated with trehalose published in Medline(accessed via EBSCOhost)and Scopus were considered.Of the 2259 studies screened,29 met the eligibility criteria.According to the SYstematic Review Center for Laboratory Animal Experiment(SYRCLE)risk of bias tool,we reported 22 out of 29 studies with a high risk of bias.The present findings support the purported role of trehalose in autophagic flux and protein refolding.This review identified several other lesser-known pathways,including modifying amyloid precursor protein processing,inhibition of reactive gliosis,the integrity of the blood-brain barrier,activation of growth factors,upregulation of the downstream antioxidant signaling pathway,and protection against mitochondrial defects.The absence of adverse events and improvements in the outcome parameters were observed in some studies,which supports the transition to human clinical trials.It is possible to conclude that trehalose exerts its neuroprotective effects through both direct and indirect pathways.However,heterogeneous methodologies and outcome measures across the studies rendered it impossible to derive a definitive conclusion.Translational studies on trehalose would need to clarify three important questions:1)bioavailability with oral administration,2)optimal time window to confer neuroprotective benefits,and 3)optimal dosage to confer neuroprotection.展开更多
Immune-mediated mechanisms are involved in the pathogenesis of both cerebral vasculitis and Parkinson’s disease（PD, brainstem-predominant Lewy pathology）, but the presentation of cerebral vasculitis with comorbid L...Immune-mediated mechanisms are involved in the pathogenesis of both cerebral vasculitis and Parkinson’s disease（PD, brainstem-predominant Lewy pathology）, but the presentation of cerebral vasculitis with comorbid Lewy pathology has not yet been reported. Here we present a case of pathologically confirmed vasculitis in a 73-year-old male patient whose postmortem examination revealed Lewy pathology diagnostic of PD. This case study suggests a comorbidity of cerebral vasculitis and Lewy pathology, as well as potential pathogenic interactions between these two disorders with immune-mediated mechanisms.展开更多
Main text Fibrillar aggregates ofα-synuclein(αSyn)play a key role in the pathogenesis of Parkinson’s disease(PD)and other synucleinopathies,making them critical targets for diagnostic approaches.In this context,see...Main text Fibrillar aggregates ofα-synuclein(αSyn)play a key role in the pathogenesis of Parkinson’s disease(PD)and other synucleinopathies,making them critical targets for diagnostic approaches.In this context,seed amplification assays(SAAs)have emerged as a promising diagnostic technique by exploiting the self-propagating nature of misfoldedαSyn aggregates.SAAs have been successfully used to detectαSyn in various biological samples,including cerebrospinal fluid(CSF),skin,and blood[1].Among these,blood-based diagnostics are particularly suitable for early detection and disease monitoring due to their non-invasive nature.However,the presence of numerous components,such as albumin and other inhibitory proteins,complicates the implementation of SAA in blood samples[2].展开更多
Sleep disturbances are common in synucleinopathies such as Parkinson’s disease(PD)and dementia with Lewy bodies(DLB)suggesting a central role in their pathophysiology and progression.Isolated REM sleep behavior disor...Sleep disturbances are common in synucleinopathies such as Parkinson’s disease(PD)and dementia with Lewy bodies(DLB)suggesting a central role in their pathophysiology and progression.Isolated REM sleep behavior disorder(iRBD),a parasomnia,frequently precedes PD and DLB and is now regarded as a prodromal synucleinopathy[1].The biological clock,regulated by clock genes and secretion of the hormone melatonin,coordinates various systems including sleep,metabolism,immune and endocrine function[2].Dysregulation of melatonin levels and clock gene expression rhythms has been reported in iRBD and PD[3,4],with mixed findings,and has not yet been studied in DLB.There is a need for clinical and biological markers that predict the risk of phenoconversion in patients with iRBD,and their trajectory towards either DLB or PD.展开更多
Synucleinopathies and tauopathies are neurodegenerative disorders characterized by the pathological accumulation ofα-synuclein(α-syn)and tau proteins,respectively.These disorders are traditionally managed with sympt...Synucleinopathies and tauopathies are neurodegenerative disorders characterized by the pathological accumulation ofα-synuclein(α-syn)and tau proteins,respectively.These disorders are traditionally managed with symptomatic treatments without addressing the underlying pathologies.Recent advancements in passive immunotherapies,notably the FDA approval of the amyloid-beta(Aβ)-targeting antibody lecanemab,have sparked new hope in directly targeting pathological proteins.However,unlike the extracellular Aβpathology,immunotherapies aimed atα-syn and tau,which predominantly form intracellular inclusions,face substantial challenges.To date,the therapeutic efficacy of fiveα-syn and 14 tau antibodies has been assessed in patients with synucleinopathies and tauopathies.These immunizations have demonstrated promising preclinical outcomes in alleviating pathological and behavioral deficits,but have not yielded significant clinical improvements in symptoms or measurable biomarkers.Therefore,a clear understanding of potential causes for the discrepancies between preclinical successes and clinical outcomes is critical for the successful translation of immunotherapy in the future.In this review,we examine existing passive immunotherapeutic strategies targetingα-syn and tau,specifically in patients with Alzheimer’s disease and Parkinson’s disease.Lessons learned from initial trial failures are also discussed,including refinement of animal models,inclusion and stratification of participants,improvement of clinical evaluations,and development of biomarkers.Given the overlapping pathologies and clinical manifestations of synucleinopathies and tauopathies,we further explore the potential of combined therapies targeting co-pathologies,offering novel insights for future therapeutic development against these neurodegenerative disorders.展开更多
There is increasing evidence for blood-brain barrier(BBB)alterations in Parkinson’s disease(PD),the second most common neurodegenerative disorder with rapidly rising prevalence.Altered tight junction and transporter ...There is increasing evidence for blood-brain barrier(BBB)alterations in Parkinson’s disease(PD),the second most common neurodegenerative disorder with rapidly rising prevalence.Altered tight junction and transporter protein levels,accumulation ofα-synuclein and increase in inflammatory processes lead to extravasation of blood molecules and vessel degeneration.This could result in a self-perpetuating pathophysiology of inflammation and BBB alteration,which contribute to neurodegeneration.Toxin exposure orα-synuclein over-expression in animal models has been shown to initiate similar pathologies,providing a platform to study underlying mechanisms and therapeutic interventions.Here we provide a comprehensive review of the current knowledge on BBB alterations in PD patients and how rodent models that replicate some of these changes can be used to study disease mechanisms.Specific challenges in assessing the BBB in patients and in healthy controls are discussed.Finally,a potential role of BBB alterations in disease pathogenesis and possible implications for therapy are explored.The interference of BBB alterations with current and novel therapeutic strategies requires more attention.Brain region-specific BBB alterations could also open up novel opportunities to target specifically vulnerable neuronal subpopulations.展开更多
Many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterised by the accumulation of misfolded protein deposits in the brain, leading to a progressive destabilisation of t...Many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterised by the accumulation of misfolded protein deposits in the brain, leading to a progressive destabilisation of the neuronal network and neuronal death. Among the proteins that can abnormally accumulate are tau and α-synuclein, which can propagate in a prion-like manner and which upon aggregation, represent the most common intracellular proteinaceous lesions associated with neurodegeneration. For years it was thought that these intracellular proteins and their accumulation had no immediate relationship with extracellular homeostasis pathways such as the glymphatic clearance system;however, mounting evidence has now suggested that this is not the case. The involvement of the glymphatic system in neurodegenerative disease is yet to be fully defined;however, it is becoming increasingly clear that this pathway contributes to parenchymal solute clearance. Importantly, recent data show that proteins prone to intracellular accumulation are subject to glymphatic clearance, suggesting that this system plays a key role in many neurological disorders. In this review, we provide a background on the biology of tau and α-synuclein and discuss the latest findings on the cell-to-cell propagation mechanisms of these proteins. Importantly, we discuss recent data demonstrating that manipulation of the glymphatic system may have the potential to alleviate and reduce pathogenic accumulation of propagation-prone intracellular cytotoxic proteins. Furthermore, we will allude to the latest potential therapeutic opportunities targeting the glymphatic system that might have an impact as disease modifiers in neurodegenerative diseases.展开更多
Background Lysosomal dysfunction has been implicated in a number of neurodegenerative diseases such as Parkinson’s disease(PD).Various molecular,clinical and genetic studies have highlighted a central role of lysosom...Background Lysosomal dysfunction has been implicated in a number of neurodegenerative diseases such as Parkinson’s disease(PD).Various molecular,clinical and genetic studies have highlighted a central role of lysosomal pathways and proteins in the pathogenesis of PD.Within PD pathology the synaptic protein alpha-synuclein(αSyn)converts from a soluble monomer to oligomeric structures and insoluble amyloid fibrils.The aim of this study was to unravel the effect ofαSyn aggregates on lysosomal turnover,particularly focusing on lysosomal homeostasis and cathepsins.Since these enzymes have been shown to be directly involved in the lysosomal degradation ofαSyn,impairment of their enzymatic capacity has extensive consequences.Methods We used patient-derived induced pluripotent stem cells and a transgenic mouse model of PD to examine the effect of intracellularαSyn conformers on cell homeostasis and lysosomal function in dopaminergic(DA)neurons by biochemical analyses.Results We found impaired lysosomal trafficking of cathepsins in patient-derived DA neurons and mouse models withαSyn aggregation,resulting in reduced proteolytic activity of cathepsins in the lysosome.Using a farnesyltransferase inhibitor,which boosts hydrolase transport via activation of the SNARE protein ykt6,we enhanced the maturation and proteolytic activity of cathepsins and thereby decreasedαSyn protein levels.Conclusions Our findings demonstrate a strong interplay betweenαSyn aggregation pathways and function of lysosomal cathepsins.It appears thatαSyn directly interferes with the enzymatic function of cathepsins,which might lead to a vicious cycle of impairedαSyn degradation.展开更多
Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are one of the most frequent genetic causes of both familial and sporadic Parkinson’s disease (PD). Mounting evidence has demonstrated pathological similarit...Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are one of the most frequent genetic causes of both familial and sporadic Parkinson’s disease (PD). Mounting evidence has demonstrated pathological similarities between LRRK2-associated PD (LRRK2-PD) and sporadic PD, suggesting that LRRK2 is a potential disease modulator and a thera-peutic target in PD. LRRK2 mutant knock-in (KI) mouse models display subtle alterations in pathological aspects that mirror early-stage PD, including increased susceptibility of nigrostriatal neurotransmission, development of motor and non-motor symptoms, mitochondrial and autophagy-lysosomal defects and synucleinopathies. This review provides a rationale for the use of LRRK2 KI mice to investigate the LRRK2-mediated pathogenesis of PD and implications from current findings from different LRRK2 KI mouse models, and ultimately discusses the therapeutic potentials against LRRK2-associated pathologies in PD.展开更多
Parkinson's disease(PD)is a neurodegenerative disorder characterized by progressive motor disturbances and affects more than 1%of the worldwide population.Diagnosis of PD relies on clinical history and physical ex...Parkinson's disease(PD)is a neurodegenerative disorder characterized by progressive motor disturbances and affects more than 1%of the worldwide population.Diagnosis of PD relies on clinical history and physical examination,but misdiagnosis is common in early stages.Despite considerable progress in understanding PD pathophysiology,including genetic and biochemical causes,diagnostic approaches lack accuracy and interventions are restricted to symptomatic treatments.Identification of biomarkers for PD may allow early and more precise diagnosis and monitoring of dopamine replacement strategies and disease-modifying treatments.Increasing evidence suggests that autophagic dysregulation causes the accumulation of abnormal proteins,such as aberrantα-synuclein,a protein critical to PD pathogenesis.Mutations in the GBA gene are a major PD risk factor andβ-glucocerebrosidase(GCase)is also emerging as an important molecule in PD pathogenesis.Consequently,proteins involved in the autophagy-lysosome pathway and GCase protein levels and activity are prime targets for the research and development of new PD biomarkers.The studies so far in PD biological material have yielded some consistent results,particularly regarding the levels of Hsc70,a component of the chaperone-mediated autophagy pathway,and the enzymatic activity of GCase in GBA mutation carriers.In the future,larger longitudinal studies,corroborating previous research on possible biomarker candidates,as well as extending the search for possible candidates for other lysosomal components,may yield more definitive results.展开更多
基金supported by Hirosaki University Priority Research Grant for Future Innovation(YM),JSPS KAKENHI(24K10654(YM),20K16592(TK),23K06802(FM)and 23K24209(KW))the Collaborative Research Project of the Brain Research Institute,Niigata University(YM,AK),AMED(JP23wm0425019 and 24zf0127012(AK))+1 种基金Grants-in-Aid from the Research Committee of CNS Degenerative Diseases,Research on Policy PlanningEvaluation for Rare and Intractable Diseases,Health,Labour and Welfare Sciences Research Grants,the Ministry of Health,Labour and Welfare,Japan(AK).CB is supported by Alzheimer’s Research UK and the MSA Trust.
文摘Background Despite increasing in vitro research,direct evidence of how abnormalα-synuclein(α-Syn)dysregulates vesicular transport and synaptic function in the human brain is lacking.Methods We performed a transcriptome analysis using brain tissues from a multiple system atrophy(MSA)mouse model,which develops humanα-Syn-positive glial cytoplasmic inclusion-like structures and neuronal cytoplasmic inclusion-like structures after tamoxifen injection.We then performed histologic and biochemical analyses using brain samples from 71 human cases(Parkinson’s disease,n=10;dementia with Lewy bodies[DLB],n=19;MSA,n=15;control:n=27),a human blood sample(control:n=1),and cultured cells.Results Based on the transcriptome of the MSA mouse model,we identified 10 vesicular transport proteins,including synaptotagmin 13(SYT13),that might interact withα-Syn.Immunohistochemistry using human brain samples demonstrated that of the 10 vesicular transport proteins identified in the transcriptome analysis,only SYT13 was incorporated into both Lewy bodies and glial cytoplasmic inclusions.Proximity ligation assays revealed that SYT13 exhibited a higher degree of interactions with phosphorylatedα-Syn than with endogenousα-Syn.Immunoprecipitation confirmed that SYT13 bound predominantly to phosphorylatedα-Syn,SYT1,and the soluble N-ethylmaleimide-sensitive attachment protein receptor(SNARE)complexes.Filter trap assays revealed interactions between SYT13 and soluble toxicβ-sheet-richα-Syn oligomers.Furthermore,fraction analysis showed a significant increase of SYT13 protein levels at the synapses in DLB and MSA.Notably,a correlation was observed between the levels of SYT13 and aggregatedα-Syn at the synapses.SYT13 was observed to regulate extracellular vesicle release in association with SYT1 and the SNARE complexes in SH-SY5Y cells.SYT13 overexpression in SH-SY5Y cells impaired extracellular vesicle release.Consistently,the numbers of extracellular vesicles were significantly reduced in the brain homogenates of DLB and MSA cases compared with those in controls.Conclusions Abnormalα-Syn impairs extracellular vesicle release through interactions with SYT13 in synucleinopathies.Our findings provide insights into therapeutic strategies for alleviating dysregulations of vesicular transport and synaptic function in patients with synucleinopathies.
文摘The discovery of diagnostic and prognostic biomarkers for neurodegenerative diseases represents an unmet clinical challenge. For example, the diagnosis of Parkinson's disease (PD) relies mainly on the presence of clinical symptoms. Therefore, the identification and use of novel PD biomarkers would allow the application of disease-modifying treatments at the very early stages of neurodegeneration. The presynaptic protein, α-synuclein, has been genetically and biochemically linked with PD pathogenesis and has been considered as a potential biomarker for the diagnosis of PD and the related synucleinopathies. The vast majority of studies have assessed the measurement of α-synuclein, alone or in combination with other biomarkers in the cerebrospinal fluid (CSF), since it is the biofluid that most closely reflects the pathophysiology of the brain. The diagnostic value of the monomericα-synuclein but also the oligomeric, the phosphorylated and the aggregated forms of the protein has been evaluated using a variety of immunoassays. The results have so far been reproducible but the assays used are still lacking the required diagnostic accuracy. Recent reports have shown that Protein misfolding cyclic amplification is a technique that has the potential to detect α-synuclein seeds in samples of CSF with high sensitivity and across different synucleinopathies. In an effort to increase the source of biomarker for PD and related synucleinopathies,α-synuclein has also been measured in neuronal exosomes, small vesicles of endosomal origin that are secreted from neurons into the CSF or the periphery. The potential diagnostic value of exosomes stems from the notion that exosomes carry a disease-specific repertoire of marker proteins. Therefore, the assessment of exosome-associated α-synuclein species may also open up new avenues for disease diagnosis in different synucleinopathies.
基金supported by the National Natural Science Foundation of China(82371273,81430025,U1801681 to J-Y.L.and W.L.)the Key Field Research Development Program of Guangdong Province(2018B030337001)+4 种基金the Swedish Research Council(2019-01551,2023-02216)ParkinsonFonden(1351/21,1421/22,1494/23)the Strategic Research Area Multipark(Multidisciplinary research in Parkinson’s disease at Lund University)Hjarnfonden(FO2022-0282,FO2023-0397,PS2018-0062)Svenska Sällskapet för Medicinsk Forskning(SSMF,P18-0194).
文摘Proteinopathy,defined as the abnormal accumulation of proteins that eventually leads to cell death,is one of the most significant pathological features of neurodegenerative diseases.Tauopathies,represented by Alzheimer’s disease(AD),and synucleinopathies,represented by Parkinson’s disease(PD),show similarities in multiple aspects.AD manifests extrapyramidal symptoms while dementia is also a major sign of advanced PD.We and other researchers have sequentially shown the cross-seeding phenomenon ofα-synuclein(α-syn)and tau,reinforcing pathologies between synucleinopathies and tauopathies.The highly overlapping clinical and pathological features imply shared pathogenic mechanisms between the two groups of disease.The diagnostic and therapeutic strategies seemingly appropriate for one distinct neurodegenerative disease may also apply to a broader spectrum.Therefore,a clear understanding of the overlaps and divergences between tauopathy and synucleinopathy is critical for unraveling the nature of the complicated associations among neurodegenerative diseases.In this review,we discuss the shared and diverse characteristics of tauopathies and synucleinopathies from aspects of genetic causes,clinical manifestations,pathological progression and potential common therapeutic approaches targeting the pathology,in the aim to provide a timely update for setting the scheme of disease classification and provide novel insights into the therapeutic development for neurodegenerative diseases.
基金supported by the China-US Biomedical Collaborative Research Program,No.81361120393(to CTZ)the National Natural Science Foundation of China,No.81401135(to PW),81671239(to CTZ)the Shanghai Sailing Program,No.18YF1403100(to JJG)
文摘Idiopathic rapid eye movement sleep behavior disorder(iRBD) is often a precursor to neurodegenerative disease. However, voxel-based morphological studies evaluating structural abnormalities in the brains of iRBD patients are relatively rare. This study aimed to explore cerebral structural alterations using magnetic resonance imaging and to determine their association with clinical parameters in iRBD patients. Brain structural T1-weighted MRI scans were acquired from 19 polysomnogram-confirmed iRBD patients(male:female 16:3; mean age 66.6 ± 7.0 years) and 20 age-matched healthy controls(male:female 5:15; mean age 63.7 ± 5.9 years). Gray matter volume(GMV) data were analyzed based on Statistical Parametric Mapping 8, using a voxel-based morphometry method and two-sample t-test and multiple regression analysis. Compared with controls, iRBD patients had increased GMV in the middle temporal gyrus and cerebellar posterior lobe, but decreased GMV in the Rolandic operculum, postcentral gyrus, insular lobe, cingulate gyrus, precuneus, rectus gyrus, and superior frontal gyrus. iRBD duration was positively correlated with GMV in the precuneus, cuneus, superior parietal gyrus, postcentral gyrus, posterior cingulate gyrus, hippocampus, lingual gyrus, middle occipital gyrus, middle temporal gyrus, and cerebellum posterior lobe. Furthermore, phasic chin electromyographic activity was positively correlated with GMV in the hippocampus, precuneus, fusiform gyrus, precentral gyrus, superior frontal gyrus, cuneus, inferior parietal lobule, angular gyrus, superior parietal gyrus, paracentral lobule, and cerebellar posterior lobe. There were no significant negative correlations of brain GMV with disease duration or electromyographic activity in iRBD patients. These findings expand the spectrum of known gray matter modifications in iRBD patients and provide evidence of a correlation between brain dysfunction and clinical manifestations in such patients. The protocol was approved by the Ethics Committee of Huashan Hospital(approval No. KY2013-336) on January 6, 2014. This trial was registered in the ISRCTN registry(ISRCTN18238599).
基金statutory funds provided by the Polish Ministry of Science and Higher Education for Mossakowski Medical Research Centre Polish Academy of Sciences,Warsaw,Poland(9/2018,to LS)。
文摘Astrocytes are integral components of the central nervous system,where they are involved in numerous functions critical for neuronal development and functioning,including maintenance of blood-brain barrier,formation of synapses,supporting neurons with nutrients and trophic factors,and protecting them from injury.These roles are markedly affected in the course of chronic neurodegenerative disorders,often before the onset of the disease.In this review,we summarize the recent findings supporting the hypothesis that astrocytes play a fundamental role in the processes contributing to neurodegeneration.We focus onα-synucleinopathies and tauopathies as the most common neurodegenerative diseases.The mechanisms implicated in the development and progression of these disorders appear not to be exclusively neuronal,but are often related to the astrocytic-neuronal integrity and the response of astrocytes to the altered microglial function.A profound understanding of the multifaceted functions of astrocytes and identification of their communication pathways with neurons and microglia in health and in the disease is of critical significance for the development of novel mechanism-based therapies against neurodegenerative disorders.
基金supported by the National Natural Science Foundation of China,Nos.82271447,81771382the National Key Research and Development Program of China,No.2019 YFE0115900the"New 20 Terms of Universities in Jinan,No.202228022 (all to ZZ)。
文摘α-Synuclein is a protein that mainly exists in the presynaptic terminals.Abnormal folding and accumulation of α-synuclein are found in several neurodegenerative diseases,including Parkinson’s disease.Aggregated and highly phospho rylated a-synuclein constitutes the main component of Lewy bodies in the brain,the pathological hallmark of Parkinson s disease.For decades,much attention has been focused on the accumulation of α-synuclein in the brain parenchyma rather than considering Parkinson s disease as a systemic disease.Recent evidence demonstrates that,at least in some patients,the initial α-synuclein pathology originates in the peripheral organs and spreads to the brain.Injection of α-synuclein preformed fibrils into the gastrointestinal tra ct trigge rs the gutto-brain propagation of α-synuclein pathology.However,whether α-synuclein pathology can occur spontaneously in peripheral organs independent of exogenous α-synuclein preformed fibrils or pathological α-synuclein leakage from the central nervous system remains under investigation.In this review,we aimed to summarize the role of peripheral α-synuclein pathology in the pathogenesis of Parkinson’s disease.We also discuss the pathways by which α-synuclein pathology spreads from the body to the brain.
基金supported by Dana Impak Perdana Grant(DIP-2019-007)received by NMI from Universiti Kebangsaan Malaysia.
文摘Trehalose,a unique nonreducing crystalline disaccharide,is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging,intrinsic mutations,or autophagy dysregulation.This systematic review summarizes the effects of trehalose on its underlying mechanisms in animal models of selected neurodegenerative disorders(tau pathology,synucleinopathy,polyglutamine tract,and motor neuron diseases).All animal studies on neurodegenerative diseases treated with trehalose published in Medline(accessed via EBSCOhost)and Scopus were considered.Of the 2259 studies screened,29 met the eligibility criteria.According to the SYstematic Review Center for Laboratory Animal Experiment(SYRCLE)risk of bias tool,we reported 22 out of 29 studies with a high risk of bias.The present findings support the purported role of trehalose in autophagic flux and protein refolding.This review identified several other lesser-known pathways,including modifying amyloid precursor protein processing,inhibition of reactive gliosis,the integrity of the blood-brain barrier,activation of growth factors,upregulation of the downstream antioxidant signaling pathway,and protection against mitochondrial defects.The absence of adverse events and improvements in the outcome parameters were observed in some studies,which supports the transition to human clinical trials.It is possible to conclude that trehalose exerts its neuroprotective effects through both direct and indirect pathways.However,heterogeneous methodologies and outcome measures across the studies rendered it impossible to derive a definitive conclusion.Translational studies on trehalose would need to clarify three important questions:1)bioavailability with oral administration,2)optimal time window to confer neuroprotective benefits,and 3)optimal dosage to confer neuroprotection.
文摘Immune-mediated mechanisms are involved in the pathogenesis of both cerebral vasculitis and Parkinson’s disease（PD, brainstem-predominant Lewy pathology）, but the presentation of cerebral vasculitis with comorbid Lewy pathology has not yet been reported. Here we present a case of pathologically confirmed vasculitis in a 73-year-old male patient whose postmortem examination revealed Lewy pathology diagnostic of PD. This case study suggests a comorbidity of cerebral vasculitis and Lewy pathology, as well as potential pathogenic interactions between these two disorders with immune-mediated mechanisms.
基金supported by grants from the Key Research and Development Program of Guangzhou(2023B03 J0631)Guangdong Basic and Applied Basic Research Foundation(2022B1515230004)+1 种基金Guangzhou Municipal Science and Technology Bureau’s Basic Research Program for the year 2024 jointly funded by the city and universities(2023 A03 J01331)Xinjiang Uyghur Autonomous Region Key Research and Development Project(2023B03003).
文摘Main text Fibrillar aggregates ofα-synuclein(αSyn)play a key role in the pathogenesis of Parkinson’s disease(PD)and other synucleinopathies,making them critical targets for diagnostic approaches.In this context,seed amplification assays(SAAs)have emerged as a promising diagnostic technique by exploiting the self-propagating nature of misfoldedαSyn aggregates.SAAs have been successfully used to detectαSyn in various biological samples,including cerebrospinal fluid(CSF),skin,and blood[1].Among these,blood-based diagnostics are particularly suitable for early detection and disease monitoring due to their non-invasive nature.However,the presence of numerous components,such as albumin and other inhibitory proteins,complicates the implementation of SAA in blood samples[2].
基金supported by a National Health and Medical Research Council Emerging Leadership Fellowship(2008565)the US Department of Defense Congressionally Directed Medical Research Program Early Investigator Grant(PD220061)+1 种基金supported by a National Health and Medical Research Council Leadership Fellowship(1195830)has received research funding from the Michael J.Fox Foundation and the Australian Research Council,as well as consulting for Pharmaxis Ltd.
文摘Sleep disturbances are common in synucleinopathies such as Parkinson’s disease(PD)and dementia with Lewy bodies(DLB)suggesting a central role in their pathophysiology and progression.Isolated REM sleep behavior disorder(iRBD),a parasomnia,frequently precedes PD and DLB and is now regarded as a prodromal synucleinopathy[1].The biological clock,regulated by clock genes and secretion of the hormone melatonin,coordinates various systems including sleep,metabolism,immune and endocrine function[2].Dysregulation of melatonin levels and clock gene expression rhythms has been reported in iRBD and PD[3,4],with mixed findings,and has not yet been studied in DLB.There is a need for clinical and biological markers that predict the risk of phenoconversion in patients with iRBD,and their trajectory towards either DLB or PD.
基金supported by the National Natural Science Foundation of China(U1801681 and 81901434)the Key Field Research Development Program of Guangdong Province(2018B030337001)+2 种基金Acknowledgments are also to the support of the Swedish Research Council(2023-02216)the Strong Research Environment MultiPark(Multidisciplinary research on Parkinson’s disease),Parkinsonfonden(1494/2023)The Brain Foundation(FO2023-0397).
文摘Synucleinopathies and tauopathies are neurodegenerative disorders characterized by the pathological accumulation ofα-synuclein(α-syn)and tau proteins,respectively.These disorders are traditionally managed with symptomatic treatments without addressing the underlying pathologies.Recent advancements in passive immunotherapies,notably the FDA approval of the amyloid-beta(Aβ)-targeting antibody lecanemab,have sparked new hope in directly targeting pathological proteins.However,unlike the extracellular Aβpathology,immunotherapies aimed atα-syn and tau,which predominantly form intracellular inclusions,face substantial challenges.To date,the therapeutic efficacy of fiveα-syn and 14 tau antibodies has been assessed in patients with synucleinopathies and tauopathies.These immunizations have demonstrated promising preclinical outcomes in alleviating pathological and behavioral deficits,but have not yielded significant clinical improvements in symptoms or measurable biomarkers.Therefore,a clear understanding of potential causes for the discrepancies between preclinical successes and clinical outcomes is critical for the successful translation of immunotherapy in the future.In this review,we examine existing passive immunotherapeutic strategies targetingα-syn and tau,specifically in patients with Alzheimer’s disease and Parkinson’s disease.Lessons learned from initial trial failures are also discussed,including refinement of animal models,inclusion and stratification of participants,improvement of clinical evaluations,and development of biomarkers.Given the overlapping pathologies and clinical manifestations of synucleinopathies and tauopathies,we further explore the potential of combined therapies targeting co-pathologies,offering novel insights for future therapeutic development against these neurodegenerative disorders.
基金funded by intramural funds with no role in writing of the manuscript.
文摘There is increasing evidence for blood-brain barrier(BBB)alterations in Parkinson’s disease(PD),the second most common neurodegenerative disorder with rapidly rising prevalence.Altered tight junction and transporter protein levels,accumulation ofα-synuclein and increase in inflammatory processes lead to extravasation of blood molecules and vessel degeneration.This could result in a self-perpetuating pathophysiology of inflammation and BBB alteration,which contribute to neurodegeneration.Toxin exposure orα-synuclein over-expression in animal models has been shown to initiate similar pathologies,providing a platform to study underlying mechanisms and therapeutic interventions.Here we provide a comprehensive review of the current knowledge on BBB alterations in PD patients and how rodent models that replicate some of these changes can be used to study disease mechanisms.Specific challenges in assessing the BBB in patients and in healthy controls are discussed.Finally,a potential role of BBB alterations in disease pathogenesis and possible implications for therapy are explored.The interference of BBB alterations with current and novel therapeutic strategies requires more attention.Brain region-specific BBB alterations could also open up novel opportunities to target specifically vulnerable neuronal subpopulations.
基金research fellowship awards made to IFH from Alzheimer’s Research UK(ARUK-RF2019A-003)and Parkinson’s UK(F-1902).
文摘Many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterised by the accumulation of misfolded protein deposits in the brain, leading to a progressive destabilisation of the neuronal network and neuronal death. Among the proteins that can abnormally accumulate are tau and α-synuclein, which can propagate in a prion-like manner and which upon aggregation, represent the most common intracellular proteinaceous lesions associated with neurodegeneration. For years it was thought that these intracellular proteins and their accumulation had no immediate relationship with extracellular homeostasis pathways such as the glymphatic clearance system;however, mounting evidence has now suggested that this is not the case. The involvement of the glymphatic system in neurodegenerative disease is yet to be fully defined;however, it is becoming increasingly clear that this pathway contributes to parenchymal solute clearance. Importantly, recent data show that proteins prone to intracellular accumulation are subject to glymphatic clearance, suggesting that this system plays a key role in many neurological disorders. In this review, we provide a background on the biology of tau and α-synuclein and discuss the latest findings on the cell-to-cell propagation mechanisms of these proteins. Importantly, we discuss recent data demonstrating that manipulation of the glymphatic system may have the potential to alleviate and reduce pathogenic accumulation of propagation-prone intracellular cytotoxic proteins. Furthermore, we will allude to the latest potential therapeutic opportunities targeting the glymphatic system that might have an impact as disease modifiers in neurodegenerative diseases.
基金supported by the Deutsche Forschungsgemeinschaft(DFG),Bonn,Germany(SFB877,project B11,Grant no.:125440785)the Interdisciplinary Center for Clinical Research(IZKF)at the University Hospital of the University of Erlangen-Nuremberg(Jochen-Kalden funding programme N8)Research reported in this publication was partly supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number R01NS092823 and RF1NS109157.
文摘Background Lysosomal dysfunction has been implicated in a number of neurodegenerative diseases such as Parkinson’s disease(PD).Various molecular,clinical and genetic studies have highlighted a central role of lysosomal pathways and proteins in the pathogenesis of PD.Within PD pathology the synaptic protein alpha-synuclein(αSyn)converts from a soluble monomer to oligomeric structures and insoluble amyloid fibrils.The aim of this study was to unravel the effect ofαSyn aggregates on lysosomal turnover,particularly focusing on lysosomal homeostasis and cathepsins.Since these enzymes have been shown to be directly involved in the lysosomal degradation ofαSyn,impairment of their enzymatic capacity has extensive consequences.Methods We used patient-derived induced pluripotent stem cells and a transgenic mouse model of PD to examine the effect of intracellularαSyn conformers on cell homeostasis and lysosomal function in dopaminergic(DA)neurons by biochemical analyses.Results We found impaired lysosomal trafficking of cathepsins in patient-derived DA neurons and mouse models withαSyn aggregation,resulting in reduced proteolytic activity of cathepsins in the lysosome.Using a farnesyltransferase inhibitor,which boosts hydrolase transport via activation of the SNARE protein ykt6,we enhanced the maturation and proteolytic activity of cathepsins and thereby decreasedαSyn protein levels.Conclusions Our findings demonstrate a strong interplay betweenαSyn aggregation pathways and function of lysosomal cathepsins.It appears thatαSyn directly interferes with the enzymatic function of cathepsins,which might lead to a vicious cycle of impairedαSyn degradation.
基金Tai Hung Fai Charitable Foundation-Edwin S H Leong Research Programme for Parkinson’s DiseaseThe Henry G.Leong Endowed Professorship in Neurology+1 种基金The Donation Fund for Neurology ResearchHealth and Medical Research Fund(HMRF),Food and Health Bureau,Hong Kong S.A.R.
文摘Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are one of the most frequent genetic causes of both familial and sporadic Parkinson’s disease (PD). Mounting evidence has demonstrated pathological similarities between LRRK2-associated PD (LRRK2-PD) and sporadic PD, suggesting that LRRK2 is a potential disease modulator and a thera-peutic target in PD. LRRK2 mutant knock-in (KI) mouse models display subtle alterations in pathological aspects that mirror early-stage PD, including increased susceptibility of nigrostriatal neurotransmission, development of motor and non-motor symptoms, mitochondrial and autophagy-lysosomal defects and synucleinopathies. This review provides a rationale for the use of LRRK2 KI mice to investigate the LRRK2-mediated pathogenesis of PD and implications from current findings from different LRRK2 KI mouse models, and ultimately discusses the therapeutic potentials against LRRK2-associated pathologies in PD.
文摘Parkinson's disease(PD)is a neurodegenerative disorder characterized by progressive motor disturbances and affects more than 1%of the worldwide population.Diagnosis of PD relies on clinical history and physical examination,but misdiagnosis is common in early stages.Despite considerable progress in understanding PD pathophysiology,including genetic and biochemical causes,diagnostic approaches lack accuracy and interventions are restricted to symptomatic treatments.Identification of biomarkers for PD may allow early and more precise diagnosis and monitoring of dopamine replacement strategies and disease-modifying treatments.Increasing evidence suggests that autophagic dysregulation causes the accumulation of abnormal proteins,such as aberrantα-synuclein,a protein critical to PD pathogenesis.Mutations in the GBA gene are a major PD risk factor andβ-glucocerebrosidase(GCase)is also emerging as an important molecule in PD pathogenesis.Consequently,proteins involved in the autophagy-lysosome pathway and GCase protein levels and activity are prime targets for the research and development of new PD biomarkers.The studies so far in PD biological material have yielded some consistent results,particularly regarding the levels of Hsc70,a component of the chaperone-mediated autophagy pathway,and the enzymatic activity of GCase in GBA mutation carriers.In the future,larger longitudinal studies,corroborating previous research on possible biomarker candidates,as well as extending the search for possible candidates for other lysosomal components,may yield more definitive results.
