Could a Common Mechanism of Protein Degradation Impairment Underlie Many Neurodegenerative Diseases?
Author ORCID Identifier
Document Type
Article
Publication Date
2018
College/Unit
School of Medicine
Department/Program/Center
Biochemistry
Abstract
At the cellular level, many neurodegenerative diseases (NDs), often considered proteinopathies, are characterized by the accumulation of misfolded and damaged proteins into large insoluble aggregates. Prominent species that accumulate early and play fundamental roles in disease pathogenesis are amyloid β (Aβ) and tau in Alzheimer disease, α-synuclein (α-syn) in Parkinson disease, and polyQ-expanded huntingtin (Htt) in Huntington disease. Although significant efforts have focused on how the cell deals with these protein aggregates, why is it that these misfolded proteins are not degraded normally in the first place? A vast body of literature supports the notion that the cell’s protein degradation system for individual proteins—the ubiquitin proteasome system (UPS)—does not function sufficiently in many NDs. The proteasome itself has received significant focus for years due to its obvious failure to degrade misfolded proteins in ND, but no general mechanism has been uncovered. We have recently found that specific pathologically relevant oligomers can potently and directly inhibit the proteasome. What is most interesting is that the misfolded protein’s primary amino acid sequence was irrelevant to its ability to inhibit. Instead, the culprit is the 3-dimensional shape of the misfolded oligomers. It turns out that many misfolded proteins in ND can take on this proteasome-impairing shape suggesting that there could be a common mechanism for UPS impairment in many NDs. The proteasome is already an important target for treating cancer, could it also be targeted to broadly treat ND?
Digital Commons Citation
Smith, David M., "Could a Common Mechanism of Protein Degradation Impairment Underlie Many Neurodegenerative Diseases?" (2018). Faculty & Staff Scholarship. 1400.
https://researchrepository.wvu.edu/faculty_publications/1400
Source Citation
Smith, D. M. (2018). Could a Common Mechanism of Protein Degradation Impairment Underlie Many Neurodegenerative Diseases? Journal of Experimental Neuroscience, 12, 117906951879467. https://doi.org/10.1177/1179069518794675
Comments
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