The Role of the Ubiquitin-Proteasome Pathway in Neurodegenerative Disorders

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.