퇴행성 신경계 질환에서 Ubiquitin-Proteasome 경로의 역할

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-κB by pro-inflammatory signals. Dysfunction of this pathway may aberrantly affect the signaling of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), which are abundantly present in AD brains. To address this, chemokine expression was measured as a readout for IL-1β and TNF-α signaling in human astrocytes. Proteasome inhibitors, MG-132 and lactacystin, suppressed IL-1β and TNF-α-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-1β and TNF-α 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.Key Words: Astrocytes, Neurodegenerative disorders, Neuroimmunology, Cytokines, MG-132