The role of α-synuclein prion strains in Parkinson’s disease and multiple system atrophy

Khedmatgozar, Chase R.; Holec, Sara A. M.; Woerman, Amanda L.

doi:10.1371/journal.ppat.1011920

PLoS Pathog

2024

DOI: 10.1371/journal.ppat.1011920

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The role of α-synuclein prion strains in Parkinson’s disease and multiple system atrophy

Chase R. Khedmatgozar,

Sara A. M. Holec,

Amanda L. Woerman

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2024

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Cited by 3 publications

References 29 publications

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Current insights and assumptions on α-synuclein in Lewy body disease

Leak,

Clark,

Abbas

et al. 2024

Acta Neuropathol

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Lewy body disorders are heterogeneous neurological conditions defined by intracellular inclusions composed of misshapen α-synuclein protein aggregates. Although α-synuclein aggregates are only one component of inclusions and not strictly coupled to neurodegeneration, evidence suggests they seed the propagation of Lewy pathology within and across cells. Genetic mutations, genomic multiplications, and sequence polymorphisms of the gene encoding α-synuclein are also causally linked to Lewy body disease. In nonfamilial cases of Lewy body disease, the disease trigger remains unidentified but may range from industrial/agricultural toxicants and natural sources of poisons to microbial pathogens. Perhaps due to these peripheral exposures, Lewy inclusions appear at early disease stages in brain regions connected with cranial nerves I and X, which interface with inhaled and ingested environmental elements in the nasal or gastrointestinal cavities. Irrespective of its identity, a stealthy disease trigger most likely shifts soluble α-synuclein (directly or indirectly) into insoluble, cross-β-sheet aggregates. Indeed, β-sheet-rich self-replicating α-synuclein multimers reside in patient plasma, cerebrospinal fluid, and other tissues, and can be subjected to α-synuclein seed amplification assays. Thus, clinicians should be able to capitalize on α-synuclein seed amplification assays to stratify patients into potential responders versus non-responders in future clinical trials of α-synuclein targeted therapies. Here, we briefly review the current understanding of α-synuclein in Lewy body disease and speculate on pathophysiological processes underlying the potential transmission of α-synucleinopathy across the neuraxis.

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Current insights and assumptions on α-synuclein in Lewy body disease

Leak,

Clark,

Abbas

et al. 2024

Acta Neuropathol

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Astrocytes initiate autophagic flux and maintain cell viability after internalizing non-active native extracellular α-synuclein

Andromidas,

Mackinnon,

Myers

et al. 2024

Molecular and Cellular Neuroscience

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Liquid–liquid phase separation and conformational strains of α-Synuclein: implications for Parkinson’s disease pathogenesis

Ruiz-Ortega,

Wilkaniec,

Adamczyk

2024

Front. Mol. Neurosci.

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Parkinson’s disease (PD) and other synucleinopathies are characterized by the aggregation and deposition of alpha-synuclein (α-syn) in brain cells, forming insoluble inclusions such as Lewy bodies (LBs) and Lewy neurites (LNs). The aggregation of α-syn is a complex process involving the structural conversion from its native random coil to well-defined secondary structures rich in β-sheets, forming amyloid-like fibrils. Evidence suggests that intermediate species of α-syn aggregates formed during this conversion are responsible for cell death. However, the molecular events involved in α-syn aggregation and its relationship with disease onset and progression remain not fully elucidated. Additionally, the clinical and pathological heterogeneity observed in various synucleinopathies has been highlighted. Liquid–liquid phase separation (LLPS) and condensate formation have been proposed as alternative mechanisms that could underpin α-syn pathology and contribute to the heterogeneity seen in synucleinopathies. This review focuses on the role of the cellular environment in α-syn conformational rearrangement, which may lead to pathology and the existence of different α-syn conformational strains with varying toxicity patterns. The discussion will include cellular stress, abnormal LLPS formation, and the potential role of LLPS in α-syn pathology.

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The role of α-synuclein prion strains in Parkinson’s disease and multiple system atrophy

Cited by 3 publications

References 29 publications

Current insights and assumptions on α-synuclein in Lewy body disease

Current insights and assumptions on α-synuclein in Lewy body disease

Astrocytes initiate autophagic flux and maintain cell viability after internalizing non-active native extracellular α-synuclein

Liquid–liquid phase separation and conformational strains of α-Synuclein: implications for Parkinson’s disease pathogenesis

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