The expression level of alpha-synuclein in different neuronal populations is the primary determinant of its prion-like seeding

Courte, Josquin; Bousset, Luc; Boxberg, Ysander von; Villard, Catherine; Melki, Ronald; Peyrin, Jean‐Michel

doi:10.1038/s41598-020-61757-x

Cited by 58 publications

(73 citation statements)

References 77 publications

(79 reference statements)

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“…Interestingly, the quantity of aSyn released to the cell media is correlated with the intracellular levels [ 184 ]. In addition, the susceptibility of different neuronal populations is linked to their endogenous aSyn expression level, establishing that endogenous aSyn levels play a key role in aSyn prion-like seeding [ 185 ].…”

Section: Mechanisms For Cell-to-cell Transfer Of Asynmentioning

confidence: 99%

Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies

Brás

Outeiro

2021

Cells

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The accumulation of misfolded alpha-synuclein (aSyn) throughout the brain, as Lewy pathology, is a phenomenon central to Parkinson’s disease (PD) pathogenesis. The stereotypical distribution and evolution of the pathology during disease is often attributed to the cell-to-cell transmission of aSyn between interconnected brain regions. The spreading of conformationally distinct aSyn protein assemblies, commonly referred as strains, is thought to result in a variety of clinically and pathologically heterogenous diseases known as synucleinopathies. Although tremendous progress has been made in the field, the mechanisms involved in the transfer of these assemblies between interconnected neural networks and their role in driving PD progression are still unclear. Here, we present an update of the relevant discoveries supporting or challenging the prion-like spreading hypothesis. We also discuss the importance of aSyn strains in pathology progression and the various putative molecular mechanisms involved in cell-to-cell protein release. Understanding the pathways underlying aSyn propagation will contribute to determining the etiology of PD and related synucleinopathies but also assist in the development of new therapeutic strategies.

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Section: Mechanisms For Cell-to-cell Transfer Of Asynmentioning

confidence: 99%

Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies

Brás

Outeiro

2021

Cells

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“…Based on the fact that synucleinopathy is a common pathological characteristic of PD (Courte et al, 2020 ; Stoyka et al, 2020 ), we decided to use the single-cell transcriptomic database Dropviz.org (Saunders et al, 2018 ) to explore the relationship between the cellular localization of Snca and GWAS-implicated genes ( Figure 3 ). This database includes gene expression data for 565 transcriptionally distinct cell types across nine brain regions of the mouse, representing one of the most comprehensive, and user-friendly, single-cell databases currently available (Saunders et al, 2018 ).…”

Section: Potential Mechanisms Contributing To Synapse Loss In Pdmentioning

confidence: 99%

Molecular Mechanisms Underlying Synaptic and Axon Degeneration in Parkinson’s Disease

Gcwensa

Russell

Cowell

et al. 2021

Front. Cell. Neurosci.

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Parkinson’s disease (PD) is a progressive neurodegenerative disease that impairs movement as well as causing multiple other symptoms such as autonomic dysfunction, rapid eye movement (REM) sleep behavior disorder, hyposmia, and cognitive changes. Loss of dopamine neurons in the substantia nigra pars compacta (SNc) and loss of dopamine terminals in the striatum contribute to characteristic motor features. Although therapies ease the symptoms of PD, there are no treatments to slow its progression. Accumulating evidence suggests that synaptic impairments and axonal degeneration precede neuronal cell body loss. Early synaptic changes may be a target to prevent disease onset and slow progression. Imaging of PD patients with radioligands, post-mortem pathologic studies in sporadic PD patients, and animal models of PD demonstrate abnormalities in presynaptic terminals as well as postsynaptic dendritic spines. Dopaminergic and excitatory synapses are substantially reduced in PD, and whether other neuronal subtypes show synaptic defects remains relatively unexplored. Genetic studies implicate several genes that play a role at the synapse, providing additional support for synaptic dysfunction in PD. In this review article we: (1) provide evidence for synaptic defects occurring in PD before neuron death; (2) describe the main genes implicated in PD that could contribute to synapse dysfunction; and (3) show correlations between the expression of Snca mRNA and mouse homologs of PD GWAS genes demonstrating selective enrichment of Snca and synaptic genes in dopaminergic, excitatory and cholinergic neurons. Altogether, these findings highlight the need for novel therapeutics targeting the synapse and suggest that future studies should explore the roles for PD-implicated genes across multiple neuron types and circuits.

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“…Several aggregation events may occur in different tissues within any given time frame, thus leading to the observation we report. The exactitude with which different strains template αSyn aggregation may also depend on the regional and/or cellular context; in particular, αSyn expression levels [ 55 ] may represent another explanation for our findings.…”

Section: Discussionmentioning

confidence: 99%

Seeding Propensity and Characteristics of Pathogenic αSyn Assemblies in Formalin-Fixed Human Tissue from the Enteric Nervous System, Olfactory Bulb, and Brainstem in Cases Staged for Parkinson’s Disease

Fenyi¹,

Duyckaerts²,

Bousset³

et al. 2021

Cells

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We investigated α-synuclein’s (αSyn) seeding activity in tissue from the brain and enteric nervous system. Specifically, we assessed the seeding propensity of pathogenic αSyn in formalin-fixed tissue from the gastric cardia and five brain regions of 29 individuals (12 Parkinson’s disease, 8 incidental Lewy body disease, 9 controls) using a protein misfolding cyclic amplification assay. The structural characteristics of the resultant αSyn assemblies were determined by limited proteolysis and transmission electron microscopy. We show that fixed tissue from Parkinson’s disease (PD) and incidental Lewy body disease (ILBD) seeds the aggregation of monomeric αSyn into fibrillar assemblies. Significant variations in the characteristics of fibrillar assemblies derived from different regions even within the same individual were observed. This finding suggests that fixation stabilizes seeds with an otherwise limited seeding propensity, that yield assemblies with different intrinsic structures (i.e., strains). The lag phase preceding fibril assembly for patients ≥80 was significantly shorter than in other age groups, suggesting the existence of increased numbers of seeds or a higher seeding potential of pathogenic αSyn with time. Seeding activity did not diminish in late-stage disease. No statistically significant difference in the seeding efficiency of specific regions was found, nor was there a relationship between seeding efficiency and the load of pathogenic αSyn in a particular region at a given neuropathological stage.

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The expression level of alpha-synuclein in different neuronal populations is the primary determinant of its prion-like seeding

Cited by 58 publications

References 77 publications

Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies

Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies

Molecular Mechanisms Underlying Synaptic and Axon Degeneration in Parkinson’s Disease

Seeding Propensity and Characteristics of Pathogenic αSyn Assemblies in Formalin-Fixed Human Tissue from the Enteric Nervous System, Olfactory Bulb, and Brainstem in Cases Staged for Parkinson’s Disease

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