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Proteolytic α-Synuclein Cleavage in Health and Disease

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...

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Autores principales: Bluhm, Alexandra, Schrempel, Sarah, von Hörsten, Stephan, Schulze, Anja, Roßner, Steffen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196865/
https://www.ncbi.nlm.nih.gov/pubmed/34064208
http://dx.doi.org/10.3390/ijms22115450
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author Bluhm, Alexandra
Schrempel, Sarah
von Hörsten, Stephan
Schulze, Anja
Roßner, Steffen
author_facet Bluhm, Alexandra
Schrempel, Sarah
von Hörsten, Stephan
Schulze, Anja
Roßner, Steffen
author_sort Bluhm, Alexandra
collection PubMed
description 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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spelling pubmed-81968652021-06-13 Proteolytic α-Synuclein Cleavage in Health and Disease Bluhm, Alexandra Schrempel, Sarah von Hörsten, Stephan Schulze, Anja Roßner, Steffen Int J Mol Sci Review 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. MDPI 2021-05-21 /pmc/articles/PMC8196865/ /pubmed/34064208 http://dx.doi.org/10.3390/ijms22115450 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Bluhm, Alexandra
Schrempel, Sarah
von Hörsten, Stephan
Schulze, Anja
Roßner, Steffen
Proteolytic α-Synuclein Cleavage in Health and Disease
title Proteolytic α-Synuclein Cleavage in Health and Disease
title_full Proteolytic α-Synuclein Cleavage in Health and Disease
title_fullStr Proteolytic α-Synuclein Cleavage in Health and Disease
title_full_unstemmed Proteolytic α-Synuclein Cleavage in Health and Disease
title_short Proteolytic α-Synuclein Cleavage in Health and Disease
title_sort proteolytic α-synuclein cleavage in health and disease
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196865/
https://www.ncbi.nlm.nih.gov/pubmed/34064208
http://dx.doi.org/10.3390/ijms22115450
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