Semester

Fall

Date of Graduation

2005

Document Type

Dissertation

Degree Type

PhD

College

Davis College of Agriculture, Natural Resources and Design

Department

Biochemistry

Committee Chair

Jia Luo

Abstract

Ethanol and 6-hydroxydopamine (6-OHDA), a Parkinson's disease (PD) mimetic, are two toxins to the cerebellum. This study investigated the molecular mechanisms underlying their neurotoxicities. The work in chapter 2 of this thesis focused on 6-OHDA-induced neurodegeneration. Previous studies indicate that impaired function of the endoplasmic reticulum (ER), commonly referred to as ER stress, is an important factor in the neuropathology of a wide variety of neurological disorders. This study demonstrated that 6-OHDA evoked ER-stress and led to apoptosis in SH-SY5Y neuronal cell line and cultured rat cerebellar granule neurons (CGNs). Furthermore, GSK3beta played a crucial role in mediating 6-OHDA's neurotoxicity. GSK3beta inhibitors and neurotrophic factor, such as BDNF, protected neural cells against 6-OHDA-induced cell death. The results suggest that GSK3beta is an important intermediate in proapoptotic signaling cascades that are associated with neurodegenerative disease, thus providing a potential taget site amenable to pharmacological intervention. The work in chapter 3 explored the intracellular signaling pathway that responds to ethanol-induced damage to the cerebellum. Numerous studies have found that early developmental exposure to ethanol caused profound damage to the cerebellum, leading to significant reduction in cerebellum volume, weight and protein content. PACT (Rax)/PKR/eIF2alpha is an important signal transducing pathway which controls the protein synthesis initiation response to different stimuli. Previous studies have shown that ethanol exposure decreases the protein content in rat cerebellum and inhibits protein synthesis initiation in rat heart, liver and skeletal muscle. This study demonstrated that the expressions of PACT (Rax)/PKR/eIF2alpha are developmentally regulated in rat developing cerebellum; ethanol exposure promotes the association of PACT (Rax) with PKR. Ethanol-induced interaction between PACT(Rax) and PKR leads to phosphorylation of eIF2alpha and protein synthesis initiation inhibition. This inhibition can be enhanced by over-expression of PACT (Rax) and reversed by a mutated PACT (Rax) gene at serine 18 or PKR inhibitors. The results provide a novel insight into the molecular mechanism of ethanol toxicity.

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