Mitochondria are essential organelles that play a central role in cellular metabolism and physiology.Their broad range of functions include supplying energy,regulating signaling pathways,and maintaining control of cel...Mitochondria are essential organelles that play a central role in cellular metabolism and physiology.Their broad range of functions include supplying energy,regulating signaling pathways,and maintaining control of cell proliferation and apoptosis.As defective mitochondria can perturb cellular homeostasis,quality control mechanisms have evolved to preserve mitochondrial fidelity in response to stress and aging(Palikaras et al.,2018).Persistent defects,however,trigger elimination of the entire organelle by an evolutionarily conserved set of cellular processes that specifically remove dysfunctional or surplus mitochondria.This selective degradation of the mitochondria through autophagy,termed mitophagy,is important in fine-tuning mitochondrial number.展开更多
The fundamental role that alpha-synuclein(aSyn)plays in the pathogenesis of neurodegenerative synucleinopathies,including Parkinson’s disease,dementia with Lewy bodies,and multiple system atrophy,is a well-accepted f...The fundamental role that alpha-synuclein(aSyn)plays in the pathogenesis of neurodegenerative synucleinopathies,including Parkinson’s disease,dementia with Lewy bodies,and multiple system atrophy,is a well-accepted fact.A wealth of experimental evidence has linked this relatively small but ubiquitously expressed protein to a plethora of cytopathologic mechanisms and suggests that aSyn may be capable of seeding the progressive spread of synucleinopathy throughout the brain.Beyond the synucleinopathies,the abnormal deposition of aSyn is frequently seen in a variety of other neurodegenerative proteinopathies including Alzheimer’s disease.In spite of the fact that the frequency of concomitant aSyn pathology in these disorders is such that it can be considered the rule rather than the exception,the potential role that aSyn may have in these disorders has received relatively little attention.In this article we postulate that aSyn may in fact be a key protein in driving the pathogenic processes in neurodegenerative comorbidities.In addition to reviewing the frequency of concomitant deposition of aSyn in the neurodegenerative proteinopathies,we also consider our current understanding of the interaction of aSyn with other neurodegenerative disease-associated proteins,including tau,TDP-43,amyloid-βand prion protein,in the context of neuropathologic studies describing the anatomical sites of potential concomitant pathology.We conclude that a growing body of evidence,encompassing neuropathology studies in human brain,animal models of concomitant proteinopathies and studies employing sophisticated methods of probing protein-protein interaction,cumulatively suggest that aSyn is well positioned to exert a strong influence on the pathogenesis of the neurodegenerative comorbidities.We hope to stimulate research in this emerging field and consider that future studies exploring the contribution of aSyn to the pathogenic processes in neurodegenerative comorbidities may provide critical information pertaining to diagnosis and the development of vital disease modifying treatments for these devastating diseases.展开更多
Background Neuropathological diagnosis of argyrophilic grain disease(AGD)is currently based primarily on the combination of argyrophilic grain(AG)visualized using Gallyas-Braak silver staining,phosphorylated tau-posit...Background Neuropathological diagnosis of argyrophilic grain disease(AGD)is currently based primarily on the combination of argyrophilic grain(AG)visualized using Gallyas-Braak silver staining,phosphorylated tau-positive pretangles,coiled bodies,and ballooned neuron detection.Although AGD is common in patients with dementia and/or prominent psychiatric symptoms,whether it is a distinct neurological disease entity or a by-product of the aging process remains unclear.Methods In 1449 serial forensic autopsy cases>40 years old(823 males and 525 females,aged 40-101 years,mean age 70.0±14.1 years),we examined the frequency and comorbid pathology of AGD cases and investigated the clini-cal appearance by comparing those with non-AGD cases using the propensity score.Results Of the 1449 cases,we detected 342 AGD cases(23.6%;mean age 79.7 years;177 males and 165 females).The AGD frequency and stage increased with age(P<0.001).Among AGD cases,80(23.4%)patients had dementia,and 51(15.2%)had a history of psychiatric hospital visits.The frequency of suicide and history of psychiatric disorders were significantly higher in AGD cases than in AGD-negative cases,matched for age,sex,and comorbidity pathol-ogy,with a relative risk of suicide of 1.72(1.30-2.26).The frequency of suicide was significantly higher in AGD cases than in non-AGD cases in female but not male cases.The relative risk of suicide increased to 2.27(1.20-4.30)and 6.50(1.58-26.76)in AGD patients with Lewy and progressive supranuclear palsy pathology,respectively,and decreased to 0.88(0.38-2.10)in those with advanced AD pathology.In AGD cases,23.4%had dementia;however,the difference was not significant after controlling for age,sex,and comorbid pathology.Conclusion Our study demonstrated that AGD is a significant and isolated risk factor for psychiatric hospital visits and suicide completion.In older adults,AGs may contribute to the progression of functional impairment of the limbic system,which leads to psychiatric disorders and suicide attempts.展开更多
Background: Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution...Background: Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution of synucleinopathy correlates with the predominant clinical features, the burden of pathology does not fully explain observed differences in clinical presentation and rate of disease progression. We hypothesized that the clinical heterogeneity in MSA is a consequence of variability in the seeding activity of α-synuclein both between different patients and between different brain regions. Methods: The reliable detection of α-synuclein seeding activity derived from MSA using cell-free amplification assays remains challenging. Therefore, we conducted a systematic evaluation of 168 different reaction buffers, using an array of pH and salts, seeded with fully characterized brain homogenates from one MSA and one PD patient. We then validated the two conditions that conferred the optimal ability to discriminate between PD- and MSA-derived samples in a larger cohort of 40 neuropathologically confirmed cases, including 15 MSA. Finally, in a subset of brains, we conducted the first multi-region analysis of seeding behaviour in MSA. Results: Using our novel buffer conditions, we show that the physicochemical factors that govern the in vitro amplification of α-synuclein can be tailored to generate strain-specific reaction buffers that can be used to reliably study the seeding capacity from MSA-derived α-synuclein. Using this novel approach, we were able to sub-categorize the 15 MSA brains into 3 groups: high, intermediate and low seeders. To further demonstrate heterogeneity in α-synuclein seeding in MSA, we conducted a comprehensive multi-regional evaluation of α-synuclein seeding in 13 different regions from 2 high seeders, 2 intermediate seeders and 2 low seeders. Conclusions: We have identified unexpected differences in seed-competent α-synuclein across a cohort of neuropathologically comparable MSA brains. Furthermore, our work has revealed a substantial heterogeneity in seeding activity, driven by the PBS-soluble α-synuclein, between different brain regions of a given individual that goes beyond immunohistochemical observations. Our observations pave the way for future subclassification of MSA, which exceeds conventional clinical and neuropathological phenotyping and considers the structural and biochemical heterogeneity of α-synuclein present. Finally, our methods provide an experimental framework for the development of vitally needed, rapid and sensitive diagnostic assays for MSA.展开更多
文摘Mitochondria are essential organelles that play a central role in cellular metabolism and physiology.Their broad range of functions include supplying energy,regulating signaling pathways,and maintaining control of cell proliferation and apoptosis.As defective mitochondria can perturb cellular homeostasis,quality control mechanisms have evolved to preserve mitochondrial fidelity in response to stress and aging(Palikaras et al.,2018).Persistent defects,however,trigger elimination of the entire organelle by an evolutionarily conserved set of cellular processes that specifically remove dysfunctional or surplus mitochondria.This selective degradation of the mitochondria through autophagy,termed mitophagy,is important in fine-tuning mitochondrial number.
文摘The fundamental role that alpha-synuclein(aSyn)plays in the pathogenesis of neurodegenerative synucleinopathies,including Parkinson’s disease,dementia with Lewy bodies,and multiple system atrophy,is a well-accepted fact.A wealth of experimental evidence has linked this relatively small but ubiquitously expressed protein to a plethora of cytopathologic mechanisms and suggests that aSyn may be capable of seeding the progressive spread of synucleinopathy throughout the brain.Beyond the synucleinopathies,the abnormal deposition of aSyn is frequently seen in a variety of other neurodegenerative proteinopathies including Alzheimer’s disease.In spite of the fact that the frequency of concomitant aSyn pathology in these disorders is such that it can be considered the rule rather than the exception,the potential role that aSyn may have in these disorders has received relatively little attention.In this article we postulate that aSyn may in fact be a key protein in driving the pathogenic processes in neurodegenerative comorbidities.In addition to reviewing the frequency of concomitant deposition of aSyn in the neurodegenerative proteinopathies,we also consider our current understanding of the interaction of aSyn with other neurodegenerative disease-associated proteins,including tau,TDP-43,amyloid-βand prion protein,in the context of neuropathologic studies describing the anatomical sites of potential concomitant pathology.We conclude that a growing body of evidence,encompassing neuropathology studies in human brain,animal models of concomitant proteinopathies and studies employing sophisticated methods of probing protein-protein interaction,cumulatively suggest that aSyn is well positioned to exert a strong influence on the pathogenesis of the neurodegenerative comorbidities.We hope to stimulate research in this emerging field and consider that future studies exploring the contribution of aSyn to the pathogenic processes in neurodegenerative comorbidities may provide critical information pertaining to diagnosis and the development of vital disease modifying treatments for these devastating diseases.
文摘Background Neuropathological diagnosis of argyrophilic grain disease(AGD)is currently based primarily on the combination of argyrophilic grain(AG)visualized using Gallyas-Braak silver staining,phosphorylated tau-positive pretangles,coiled bodies,and ballooned neuron detection.Although AGD is common in patients with dementia and/or prominent psychiatric symptoms,whether it is a distinct neurological disease entity or a by-product of the aging process remains unclear.Methods In 1449 serial forensic autopsy cases>40 years old(823 males and 525 females,aged 40-101 years,mean age 70.0±14.1 years),we examined the frequency and comorbid pathology of AGD cases and investigated the clini-cal appearance by comparing those with non-AGD cases using the propensity score.Results Of the 1449 cases,we detected 342 AGD cases(23.6%;mean age 79.7 years;177 males and 165 females).The AGD frequency and stage increased with age(P<0.001).Among AGD cases,80(23.4%)patients had dementia,and 51(15.2%)had a history of psychiatric hospital visits.The frequency of suicide and history of psychiatric disorders were significantly higher in AGD cases than in AGD-negative cases,matched for age,sex,and comorbidity pathol-ogy,with a relative risk of suicide of 1.72(1.30-2.26).The frequency of suicide was significantly higher in AGD cases than in non-AGD cases in female but not male cases.The relative risk of suicide increased to 2.27(1.20-4.30)and 6.50(1.58-26.76)in AGD patients with Lewy and progressive supranuclear palsy pathology,respectively,and decreased to 0.88(0.38-2.10)in those with advanced AD pathology.In AGD cases,23.4%had dementia;however,the difference was not significant after controlling for age,sex,and comorbid pathology.Conclusion Our study demonstrated that AGD is a significant and isolated risk factor for psychiatric hospital visits and suicide completion.In older adults,AGs may contribute to the progression of functional impairment of the limbic system,which leads to psychiatric disorders and suicide attempts.
基金the Edmond J Safra Philanthropic Foundation,the Krembil Foundation,and the Rossy FoundationThe funding bodies did not take part in design of the study,in collection,analysis,or interpretation of data,or in writing the manuscript.
文摘Background: Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution of synucleinopathy correlates with the predominant clinical features, the burden of pathology does not fully explain observed differences in clinical presentation and rate of disease progression. We hypothesized that the clinical heterogeneity in MSA is a consequence of variability in the seeding activity of α-synuclein both between different patients and between different brain regions. Methods: The reliable detection of α-synuclein seeding activity derived from MSA using cell-free amplification assays remains challenging. Therefore, we conducted a systematic evaluation of 168 different reaction buffers, using an array of pH and salts, seeded with fully characterized brain homogenates from one MSA and one PD patient. We then validated the two conditions that conferred the optimal ability to discriminate between PD- and MSA-derived samples in a larger cohort of 40 neuropathologically confirmed cases, including 15 MSA. Finally, in a subset of brains, we conducted the first multi-region analysis of seeding behaviour in MSA. Results: Using our novel buffer conditions, we show that the physicochemical factors that govern the in vitro amplification of α-synuclein can be tailored to generate strain-specific reaction buffers that can be used to reliably study the seeding capacity from MSA-derived α-synuclein. Using this novel approach, we were able to sub-categorize the 15 MSA brains into 3 groups: high, intermediate and low seeders. To further demonstrate heterogeneity in α-synuclein seeding in MSA, we conducted a comprehensive multi-regional evaluation of α-synuclein seeding in 13 different regions from 2 high seeders, 2 intermediate seeders and 2 low seeders. Conclusions: We have identified unexpected differences in seed-competent α-synuclein across a cohort of neuropathologically comparable MSA brains. Furthermore, our work has revealed a substantial heterogeneity in seeding activity, driven by the PBS-soluble α-synuclein, between different brain regions of a given individual that goes beyond immunohistochemical observations. Our observations pave the way for future subclassification of MSA, which exceeds conventional clinical and neuropathological phenotyping and considers the structural and biochemical heterogeneity of α-synuclein present. Finally, our methods provide an experimental framework for the development of vitally needed, rapid and sensitive diagnostic assays for MSA.
