Proteolytic α-Synuclein Cleavage in Health and Disease.

Int J Mol Sci

Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany.

Published: May 2021

AI Article Synopsis

  • Parkinson's disease is characterized by the buildup of α-synuclein in Lewy bodies and neurites, but the exact triggers for this aggregation remain unclear.
  • Recent research highlights that factors like oxidative stress from metal ions and various chemical modifications can influence the way α-synuclein folds and how it aggregates, contributing to its toxicity.
  • The review focuses on how specific enzymes, like neurosin and calpain-1, cleave α-synuclein, affecting its properties and exploring potential links to similar protein aggregation processes in Alzheimer's disease.

Article Abstract

In Parkinson's disease, aggregates of α-synuclein within Lewy bodies and Lewy neurites represent neuropathological hallmarks. However, the cellular and molecular mechanisms triggering oligomeric and fibrillary α-synuclein aggregation are not fully understood. Recent evidence indicates that oxidative stress induced by metal ions and post-translational modifications such as phosphorylation, ubiquitination, nitration, glycation, and SUMOylation affect α-synuclein conformation along with its aggregation propensity and neurotoxic profiles. In addition, proteolytic cleavage of α-synuclein by specific proteases results in the formation of a broad spectrum of fragments with consecutively altered and not fully understood physiological and/or pathological properties. In the present review, we summarize the current knowledge on proteolytical α-synuclein cleavage by neurosin, calpain-1, cathepsin D, and matrix metalloproteinase-3 in health and disease. We also shed light on the contribution of the same enzymes to proteolytical processing of pathogenic proteins in Alzheimer's disease and report potential cross-disease mechanisms of pathogenic protein aggregation.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196865PMC
http://dx.doi.org/10.3390/ijms22115450DOI Listing

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