Chemical genetic dissection of cyclin-dependent kinase 5's role in promoting neurodegenerative pathways in Alzheimer's disease
Abstract
Alzheimer’s disease (AD) is a fatal neurodegenerative disorder that is characterized by two major hallmarks: extracellular β-amyloid plaques and intracellular neurofibrillary tangles with extensive neuronal loss. However, the exact mechanism by which neurodegeneration occur remains obscure. Previous studies have reported that cyclin-dependent kinase 5 (Cdk5) kinase activity is highly deregulated in AD patients, but how this deregulation is related to neurodegeneration is largely unknown. Therefore, my Ph.D. dissertation focuses on exploring the role of Cdk5 in regulating neurodegenerative pathways in order to identify and validate therapeutic targets for AD. First, we developed highly selective, temporal and potent Cdk5 enzymatic activator and inhibitor for dissecting its role in AD. With the aid of a chemical genetic screen and Cdk5 modulators, our studies revealed a vital role of Cdk5 in (1) inducing Golgi fragmentation via GM130 phosphorylation, (2) promoting oxidative stress and mitochondrial dysfunction via inhibitory phosphorylation of two antioxidant enzymes (Peroxiredoxin-I and -II), and (3) direct and indirect activation of JNK cascade. As Golgi fragmentation, oxidative stress, mitochondrial dysfunction, and activation of JNK cascade are the most proximal contributors to neuronal cell death in AD, our findings suggest Cdk5 as a key therapeutic target for AD. Finally, we discovered GSTP1 as a novel Cdk5-interacting partner which inhibits Cdk5 kinase activity. Interestingly, endogenous Cdk5 activities and GSTP1 levels were shown to be inversely related in various cell lines and AD brains. Our studies further demonstrated that GSTP1 directly inhibits Cdk5 by dislodging p25 and p35, and indirectly by eliminating oxidative stress. Therefore, it suggests that GSTP1 level serves as a critical determinant of Cdk5 activity and may account for the aberrant activation of Cdk5 in AD pathogenesis.
Degree
Ph.D.
Advisors
Shah, Purdue University.
Subject Area
Biochemistry|Neurosciences
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