Mechanisms Underlying the Neuropathology of huntington's disease, a multifactorial Neurodegenerative Disorder

摘要

Huntington's disease (HD) is the most common polyglutamine neurodegenerative disorder. The mutation consists of an unstable expansion of CAG repeats within the coding region of the HD gene, which expresses the protein huntingtin. Although the abnormal protein is ubiquitously expressed throughout the organism, cell degeneration occurs mainly in the brain, particularly in the striatum and cortex. The first symptoms usually appear in midlife and include cognitive deficits and motor disturbances associated with the loss of voluntary movement coordination, which progress over time. The disease is invariably fatal and there is currently no cure for affected individuals. At the neuropathological level, HD is characterized by the formation of ubiquitinated neuronal intranuclear inclusions (Nils) of mutant huntingtin.The mechanisms responsible for the selective neuronal degeneration observed in HD are complex and likely multifaceted. Indeed, mounting evidence over the past decades has indicated that glutamate-mediated excitotoxicity and dopamine (DA)-mediated toxicity, as well as metabolic impairment, mitochondrial dysfunction, oxidative stress, apoptosis and autophagy contribute to the progressive neuronal degeneration observed in the HD brain.This chapter will present an overview of the various mechanisms that are thought to contribute to the neuropathology of HD. Ultimately, a better understanding of these events will lead to the development of more effective therapeutic targets for the treatment of this devastating neurodegenerative disorder.