Structural and Functional Insights into α-Synuclein Fibril Polymorphism

Abstract

Abnormal accumulation of aggregated α-synuclein (α-Syn) is seen in a variety of neurodegenerative diseases, including Parkinson’s disease (PD), multiple system atrophy (MSA), dementia with Lewy body (DLB), Parkinson’s disease dementia (PDD), and even subsets of Alzheimer’s disease (AD) showing Lewy-body-like pathology. These synucleinopathies exhibit differences in their clinical and pathological representations, reminiscent of prion disorders. Emerging evidence suggests that α-Syn self-assembles and polymerizes into conformationally diverse polymorphs in vitro and in vivo, similar to prions. These α-Syn polymorphs arising from the same precursor protein may exhibit strain-specific biochemical properties and the ability to induce distinct pathological phenotypes upon their inoculation in animal models. In this review, we discuss clinical and pathological variability in synucleinopathies and several aspects of α-Syn fibril polymorphism, including the existence of high-resolution molecular structures and brain-derived strains. The current review sheds light on the recent advances in delineating the structure–pathogenic relationship of α-Syn and how diverse α-Syn molecular polymorphs contribute to the existing clinical heterogeneity in synucleinopathies.

The association of lipids with amyloid fibrils

“…It is a more reasonable assertion that, for a given amyloidogenic protein, a distribution of fibril morphologies characterizes the influence of lipids on fibril formation by that protein. Evidence to support this assertion arises from the observation that polymorphism of fibrils of α-Syn ( 113 , 115 , 116 ), hIAPP ( 117 ), Aβ seeded from AD brain amyloid ( 111 , 112 ) and obtained ex vivo ( 118 ), plus other proteins ( 118 , 119 ), is often found within material isolated from the same natural sample. In addition, the morphologies of Aβ filaments and aggregates are influenced by the presence of lipid membranes and their lipid composition ( 19 , 26 , 27 ).…”

Neurons with Cat’s Eyes: A Synthetic Strain of α-Synuclein Fibrils Seeding Neuronal Intranuclear Inclusions

“…Therefore, the anatomical origin of the spatial spread, its dynamics, and the affected brain regions have all attracted enormous interest to experimentally identify links between disease progression features and specific α-Syn fibril strains [15,[35][36][37][38][39][40]. For recent reviews see [41,42].…”

Cryo-EM structure of amyloid fibril formed by α-synuclein hereditary A53E mutation

“…Various evidence has shown that the synuclein fibrils of synucleinopathies, which include MSA, Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies (DLB) are distinct (Schweighauser et al, 2020). The diversity of fibril structure has also shown us that the polymorphism of fibrils can cause significant differences in biological activity and clinical pathology (Boyer et al, 2020;Healey et al, 2016;Shewmaker et al, 2011;Tycko, 2015) (Falcon et al, 2018;Mehra et al, 2021;Schweighauser et al, 2020). We hypothesize that the structural variation in fibril structures could lead to different disease pathologies, and thus plan to explore structures of mutant synuclein fibrils to elucidate the structure activity relationship of synuclein fibrils in toxicity and pathology.…”