Calpain-mediated proteolysis as driver and modulator of polyglutamine toxicity
- Among posttranslational modifications, directed proteolytic processes have the strongest impact on protein integrity. They are executed by a variety of cellular machineries and lead to a wide range of molecular consequences. Compared to other forms of proteolytic enzymes, the class of calcium-activated calpains is considered as modulator proteases due to their limited proteolytic activity, which changes the structure and function of their target substrates. In the context of neurodegeneration and - in particular - polyglutamine disorders, proteolytic events have been linked to modulatory effects on the molecular pathogenesis by generating harmful breakdown products of disease proteins. These findings led to the formulation of the \(\textit {toxic fragment hypothesis}\), and calpains appeared to be one of the key players and auspicious therapeutic targets in Huntington disease and Machado Joseph disease. This review provides a current survey of the role of calpains in proteolytic processes found in polyglutamine disorders. Together with insights into general concepts behind \(\textit {toxic fragments}\) and findings in polyglutamine disorders, this work aims to inspire researchers to broaden and deepen the knowledge in this field, which will help to evaluate calpain-mediated proteolysis as a unifying and therapeutically targetable posttranslational mechanism in neurodegeneration.
Author: | Rana Dilara Incebacak EltemurGND, Huu Phuc NguyenORCiDGND, Jonasz Jeremiasz WeberORCiDGND |
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URN: | urn:nbn:de:hbz:294-104375 |
DOI: | https://doi.org/10.3389/fnmol.2022.1020104 |
Parent Title (English): | Frontiers in molecular neuroscience |
Publisher: | Frontiers Research Foundation |
Place of publication: | Lausanne |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2023/11/21 |
Date of first Publication: | 2022/10/19 |
Publishing Institution: | Ruhr-Universität Bochum, Universitätsbibliothek |
Tag: | Open Access Fonds Huntington disease (HD); calpains; dentatorubralpallidoluysian atrophy (DRPLA); posttranslational modifications (PTMs); proteolytic cleavage; spinal and bulbar muscular atrophy (SBMA); spinocerebellar ataxia (SCA); toxic fragments |
Volume: | 15 |
Issue: | Article 1020104 |
First Page: | 1020104-1 |
Last Page: | 1020104-17 |
Note: | Article Processing Charge funded by the Deutsche Forschungsgemeinschaft (DFG) and the Open Access Publication Fund of Ruhr-Universität Bochum. |
Institutes/Facilities: | Medizinische Fakultät, Abteilung für Humangenetik |
Dewey Decimal Classification: | Technik, Medizin, angewandte Wissenschaften / Medizin, Gesundheit |
open_access (DINI-Set): | open_access |
faculties: | Medizinische Fakultät |
Licence (English): | Creative Commons - CC BY 4.0 - Attribution 4.0 International |