The Role of the Ubiquitin-Proteasome Pathway in Neurodegenerative Disorders.
- Author:
Kyungsun CHOI
1
;
Chulhee CHOI
Author Information
1. Division of Molecular Life Sciences and Center for Cell Signaling Research, Ewha Womans University, Seoul, Korea. cchoi@ewha.ac.kr
- Publication Type:Review
- Keywords:
Astrocytes;
Neurodegenerative disorders;
Neuroimmunology;
Cytokines;
MG-132
- MeSH:
Aging;
Alzheimer Disease;
Astrocytes;
Brain;
Cell Death;
Chemokine CCL5;
Cytokines;
Humans;
Interleukin-1beta;
Interleukin-8;
Negotiating;
Neurodegenerative Diseases*;
NF-kappa B;
Parkinson Disease;
Proteasome Inhibitors;
Tumor Necrosis Factor-alpha;
Ubiquitin
- From:Journal of the Korean Neurological Association
2003;21(6):573-583
- CountryRepublic of Korea
- Language:Korean
-
Abstract:
Impaired function of the Ubiquitin (Ub)/proteasome pathway is one of the molecular mechanisms underlying aging process and neurodegenerative disorders such as Parkinson's Disease and Alzheimer's Disease (AD). Among many vital cellular functions, the Ub/proteasome pathway regulates immune responses via mediating activation of NF-kappa B by pro-inflammatory signals. Dysfunction of this pathway may aberrantly affect the signaling of pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), which are abundantly present in AD brains. To address this, chemokine expression was measured as a readout for IL-1beta and TNF-alpha signaling in human astrocytes. Proteasome inhibitors, MG-132 and lactacystin, suppressed IL-1beta and TNF-alpha-induced expression of MCP-1, RANTES and IP-10, but not that of IL-8. In addition, human astrocytes underwent apoptotic cell death upon treatment with IL-1beta and TNF-alpha only in the presence of the proteasome inhibitors. These results suggest that inhibition of the Ub/proteasome pathway dysregulates pro-inflammatory cytokine signaling in human astrocytes, leading to divergent chemokine expression and enhanced cell death. Therefore, we propose that the immuno-pathologic role of astrocytes in AD brains should be re-evaluated under the circumstances of impaired function of the Ub/proteasome pathway.
