Truncation or proteolysis of α-synuclein in Parkinsonism

Abstract

Posttranslational modifications of α-synuclein, such as truncation or abnormal proteolysis, are implicated in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). A key focus of this article includes the proteases responsible for inducing truncation, the specific sites susceptible to truncation, and the resultant influence of these truncated species on the seeding and aggregation of endogenous α-synuclein. We also shed light on the unique structural attributes of these truncated species, and how these modifications can lead to distinctive forms of synucleinopathies. In addition, we explore the comparative toxic potentials of various α-synuclein species. An extensive analysis of available evidence of truncated α-synuclein species in human-synucleinopathy brains is also provided. Lastly, we delve into the detrimental impact of truncated species on key cellular structures such as the mitochondria and endoplasmic reticulum. Our article discusses enzymes involved in α-synuclein truncation, including 20 S proteasome, cathepsins, asparagine endopeptidase, caspase-1, calpain-1, neurosin/kallikrein-6, matrix metalloproteinase-1/-3, and plasmin. Truncation patterns impact α-synuclein aggregation - C-terminal truncation accelerates aggregation with larger truncations correlated with shortened aggregation lag times. N-terminal truncation affects aggregation differently based on the truncation location. C-terminally truncated α-synuclein forms compact, shorter fibrils compared to the full-length (FL) protein. N-terminally truncated monomers form fibrils similar in length to FL α-synuclein. Truncated forms show distinct fibril morphologies, increased β-sheet structures, and greater protease resistance. Misfolded α-synuclein can adopt various conformations, leading to unique aggregates and distinct synucleinopathies. Fibrils, with prion-like transmission, are potentially more toxic than oligomers, though this is still debated. Different α-synuclein variants with N- and C-terminal truncations, namely 5-140, 39-140, 65-140, 66-140, 68-140, 71-140, 1-139, 1-135, 1-133, 1-122, 1-119, 1-115, 1-110, and 1-103 have been found in PD, DLB, and MSA patients' brains. In Parkinsonism, excess misfolded α-synuclein overwhelms the proteasome degradation system, resulting in truncated protein production and accumulation in the mitochondria and endoplasmic reticulum.

Keywords: Aggregation; Parkinson’s disease; Proteolysis; Truncation; α-Synuclein.