Author(s):
Cunha-Oliveira, Teresa 
; Ferreira, Ildete L ; Rego, A Cristina
Date: 2012
Persistent ID: http://hdl.handle.net/10316/18507
Origin: Estudo Geral - Universidade de Coimbra
Subject(s): Huntington's Disease
Description
Huntington’s Disease (HD) is an autosomal dominant neurodegenerative disorder clinically
characterized by psychiatric disturbances, progressive cognitive impairment and choreiform
movements. These symptoms are associated with the selective atrophy and neuronal loss in
the striatum, cortex and hypothalamus. The disease is caused by a mutation at the
5’ terminal of the huntingtin (HTT) gene involving the expansion of CAG triplet, which
encodes for glutamine. Mutant huntingtin (mHtt) may be cleaved by proteases originating
neurotoxic fragments, and also undergoes conformational changes that lead to the formation
of protein aggregates (Gil and Rego 2008, for review). Among several mechanisms of
neurodegeneration, mHtt is related to mitochondrial dysfunction and relevant changes in
energy metabolism in both central and peripheral cells, which may underlie cell death (Gil
and Rego 2008, for review).
In this review chapter we emphasize the role of mitochondrial dysfunction in
neurodegeneration in HD, particularly centering on loss of mitochondrial activity and the
regulation of intrinsic apoptosis in central and peripheral HD human tissue or cells, and in
animal models of HD. We focus on the changes in energy metabolism, oxidative stress, the
link to transcriptional dysfunction and the regulation of intrinsic apoptosis. We further
explore the therapeutic role of promoting phosphorylation pathways through selective
inhibition of phosphatases (e.g. with FK506) and/or activation of kinase signaling cascades
mediated by neurotrophins, namely brain-derived neurotrophic factor (BDNF) and nerve
growth factor (NGF).
