Unraveling Cdk5-mediated signaling in Alzheimer's disease pathogenesis
Alzheimer's disease (AD) is the most common neurological disorder, but no current therapies successfully halt or reverse the chronic progression of AD. Multiple types of cell death are believed to synergistically contribute to the overall consequence of AD neuronal loss so that the development of AD therapy becomes relatively difficult. The deregulated cyclin-dependent kinase 5 (Cdk5), a proline-directed kinase, has been reported in AD neurons and its substrates are demonstrated to trigger a cascade of neurotoxic pathways. Our group initially identified a spectrum of potential Cdk5 targets through chemical genetic screen. Thus, my thesis research focuses on unraveling the mechanistic link between deregulated Cdk5 and the identified substrates along with the downstream Cdk5-dirven pathological pathways, which are discussed respectively in Chapter 2-4. The potential role of Cdk5 deregulation in p38 MAPK hyperactivation, which is one of the key features for AD neurons, is investigated and discussed in Chapter 2. Our group previously substantiated that Cdk5 phosphorylates and abolishes the antioxidant activity of Prdx 2, thereby aggravating oxidative stress in the pathogenesis of AD. Following this discovery, the study discussed in Chapter 2 further demonstrate that Cdk5-induced oxidative stress serves as the trigger of p38 MAPK signaling cascade and ultimate neuronal death in AD models. Chapter 3 summaries the research work that investigated the relationship between Cdk5 and the nuclear envelope protein lamin. Cdk5 directly phosphorylated lamin A and lamin B1, causing lamina dispersion and the global disorganization of nuclear envelope. This study provides the first evidence linking Cdk5 deregulation to formation of abnormal nuclei that has been observed in AD. In Chapter 4, we reported a new Cdk5-driven mechanism underlying the re-entry of cell cycle in AD neurons. Cdk5 causes Cdc25 hyperphosphorylation and activation, which triggers aberrant activation of Cdks and eventually the loss of cell cycle control under neurotoxic condition. Together, these findings unanimously point out that inhibition of Cdk5 activity effectively prevents AD neuronal death. My dissertation study supports the idea that prevention of Cdk5 deregulation would be the promising AD therapy.
Shah, Purdue University.
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