Proteolytic α-Synuclein Cleavage in Health and Disease |
| |
Authors: | Alexandra Bluhm Sarah Schrempel Stephan von Hrsten Anja Schulze Steffen Roßner |
| |
Affiliation: | 1.Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany; (A.B.); (S.S.);2.Department for Experimental Therapy, University Clinics Erlangen and Preclinical Experimental Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany;3.Department of Molecular Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, 06120 Halle/Saale, Germany; |
| |
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. |
| |
Keywords: | α -synuclein post-translational modification proteolysis Parkinson’ s disease dementia with Lewy bodies substantia nigra animal models |
|
|