دورية أكاديمية
TDP-43 pathology: From noxious assembly to therapeutic removal.
| العنوان: | TDP-43 pathology: From noxious assembly to therapeutic removal. |
|---|---|
| المؤلفون: | Keating SS; Neurodegeneration Pathobiology Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, 4072 QLD, Australia., San Gil R; Neurodegeneration Pathobiology Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, 4072 QLD, Australia., Swanson MEV; School of Biological Sciences, The University of Auckland, Auckland 1010, New Zealand; Centre for Brain Research, The University of Auckland, Auckland 1010, New Zealand., Scotter EL; School of Biological Sciences, The University of Auckland, Auckland 1010, New Zealand; Centre for Brain Research, The University of Auckland, Auckland 1010, New Zealand., Walker AK; Neurodegeneration Pathobiology Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, 4072 QLD, Australia. Electronic address: adam.walker@uq.edu.au. |
| المصدر: | Progress in neurobiology [Prog Neurobiol] 2022 Apr; Vol. 211, pp. 102229. Date of Electronic Publication: 2022 Jan 29. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Review |
| اللغة: | English |
| بيانات الدورية: | Publisher: Pergamon Press Country of Publication: England NLM ID: 0370121 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-5118 (Electronic) Linking ISSN: 03010082 NLM ISO Abbreviation: Prog Neurobiol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Oxford : Pergamon Press Original Publication: Oxford, New York, Pergamon Press. |
| مواضيع طبية MeSH: | DNA-Binding Proteins*/chemistry , DNA-Binding Proteins*/metabolism , TDP-43 Proteinopathies*/metabolism, Amyotrophic Lateral Sclerosis/metabolism ; Frontotemporal Dementia ; Humans ; Protein Folding |
| مستخلص: | Our understanding of amyotrophic lateral sclerosis and frontotemporal dementia has advanced dramatically since the discovery of cytoplasmic TAR DNA-binding protein 43 (TDP-43) inclusions as the hallmark pathology of these neurodegenerative diseases. Recent studies have provided insights into the physiological function of TDP-43 as an essential DNA-/RNA-modulating protein, and the triggers and consequences of TDP-43 dysfunction and aggregation. The formation of TDP-43 pathology is a progressive process, involving the generation of multiple distinct protein species, each with varying biophysical properties and roles in neurodegeneration. Here, we explore how the pathogenic changes to TDP-43, including mislocalisation, misfolding, aberrant liquid-liquid phase separation, stress granule assembly, oligomerisation, and post-translational modification, drive disease-associated aggregation in TDP-43 proteinopathies. We highlight how pathological TDP-43 species are formed and contribute to cellular dysfunction and toxicity, via both loss-of-function and gain-of-function mechanisms. We also review the role of protein homeostasis mechanisms, namely the ubiquitin proteasome system, autophagy-lysosome pathway, heat-shock response, and chaperone-mediated autophagy, in combating TDP-43 aggregation and discuss how their dysfunction likely promotes disease pathogenesis and progression. Finally, we evaluate pre-clinical studies aimed at enhancing TDP-43 protein clearance via these mechanisms and provide insight on promising strategies for future therapeutic advances. Harnessing the mechanisms that protect against or ameliorate TDP-43 pathology presents promising opportunities for developing disease-modifying treatments for these neurodegenerative diseases. (Copyright © 2022 Elsevier Ltd. All rights reserved.) |
| فهرسة مساهمة: | Keywords: ALS; FTD; Motor neuron disease; Neurodegeneration; Protein degradation; Proteostasis; TDP-43 proteinopathy |
| المشرفين على المادة: | 0 (DNA-Binding Proteins) 0 (TARDBP protein, human) |
| تواريخ الأحداث: | Date Created: 20220201 Date Completed: 20220321 Latest Revision: 20220531 |
| رمز التحديث: | 20240829 |
| DOI: | 10.1016/j.pneurobio.2022.102229 |
| PMID: | 35101542 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1873-5118 |
|---|---|
| DOI: | 10.1016/j.pneurobio.2022.102229 |