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Beyond the synucleinopathies:alpha synuclein as a driving force in neurodegenerative comorbidities

Translational Neurodegeneration 2019年第1期8卷 346-358页

作者： naomi p.visanji Anthony E.Lang Gabor G.Kovacs Edmond J.Safra program in parkinson’s disease and the Morton and Gloria Shulman Movement disorders clinic Toronto Western HospitalTorontoOntarioCanada Department of Laboratory Medicine and pathobiology and Tanz Centre for Research in Neurodegenerative Disease University of TorontoTorontoOntarioCanada Laboratory Medicine program&Krembil Brain Institute University Health NetworkTorontoOntarioCanada

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 *** the synucleinopathies,the abnormal deposition of aSyn is frequently seen in a variety of other neurodegenerative proteinopathies including Alzheimer’s *** 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 *** this article we postulate that aSyn may in fact be a key protein in driving the pathogenic processes in neurodegenerative *** 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 *** 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 *** 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

关键词： Amyloid-β Alpha-synuclein Alzheimer’s disease Comorbidity Dementia with Lewy bodies Multiple system atrophy Neurodegeneration parkinson’s disease prion protein progressive supranuclear palsy proteinopathy Tau TDp-43

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Alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy

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Translational Neurodegeneration 2022年第1期11卷 845-858页

作者： Ivan Martinez-Valbuena naomi p.visanji Ain Kim Heather H.C.Lau Raphaella W.L.So Sohaila Alshimemeri Andrew Gao Michael A.Seidman Maria R.Luquin Joel C.Watts Anthony E.Lang Gabor G.Kovacs Tanz Centre for Research in Neurodegenerative Diseases University of TorontoTorontoONCanada Edmond J.Safra program in pD and the Morton and Gloria Shulman Movement Disorders Clinic Toronto Western HospitalTorontoONCanada Department of Laboratory Medicine and pathobiology University of TorontoTorontoONCanada Krembil Brain Institute University Health NetworkTorontoONCanada Department of Biochemistry University of TorontoTorontoONCanada Laboratory Medicine program University Health NetworkTorontoONCanada Department of Neurology Clinica Universidad de NavarraPamplonaNavarraSpain Division of Neurology Department of MedicineKing Saud UniversityRiyadhSaudi Arabia.

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 coho

关键词： Alpha-synuclein Multiple system atrophy RT-QuIC Seeding behavior

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