The Role of Specific JNK Isoforms in Huntington’s Disease Pathogenesis
thesisposted on 20.06.2014 by Ina H. Lee
In order to distinguish essays and pre-prints from academic theses, we have a separate category. These are often much longer text based documents than a paper.
Huntington’s Disease (HD) is an autosomal dominant genetic disease caused by expansion of a polyglutamine (polyQ) tract in huntingtin (Htt) protein. Expression of polyQ-expanded Htt (polyQ-Htt) results in adult onset degeneration of selected neuronal populations, particularly in the striatum. Pathological observations from HD patients indicate that neurons affected in HD undergo a "dying back" pattern of degeneration, which is characterized by early alterations in synaptic and axonal function prior to neuronal cell death. However, mechanisms underlying axonal degeneration in HD remain unknown. The preferential vulnerability of striatal neurons in HD sharply contrasts with the ubiquitous expression of Htt, suggesting that alterations in one or more cellular processes particularly important for the function and survival of these neurons play a central role in HD pathogenesis. The unique morphology of neurons renders these cells distinctly vulnerable to alterations in mechanisms underlying axonal function and maintenance, including fast axonal transport (FAT) and kinase-based signaling mechanisms. Aberrant patterns of protein phosphorylation have been found in association with HD, and led to studies demonstrating that polyQ-Htt activates protein kinases, and that these kinases may be involved in regulation of FAT. Prior studies in isolated squid axoplasm showed polyQ-Htt inhibits FAT through a mechanism involving activation of JNK. The work put forth here provides evidence that polyQ-Htt induced deficits in axonal transport are mediated by neural specific JNK isoform 3, and not the ubiquitous isoform 1. Based on these findings, we propose that polyQ-Htt induced activation of JNK3, and not JNK1, represents a critical pathogenic event underlying axonal degeneration in HD.