Mitochondria in Huntington's disease.
Huntington's disease (HD) is an inherited progressive neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits and psychiatric disturbances. The disease is caused by an abnormal expansion of a CAG repeat located in exon 1 of the gene encoding the huntingtin protein (Htt) that confers a toxic function to the protein. The most striking neuropathological change in HD is the preferential loss of medium spiny GABAergic neurons in the striatum. The mechanisms underlying striatal vulnerability in HD are unknown, but compelling evidence suggests that mitochondrial defects may play a central role. Here we review recent findings supporting this hypothesis. Studies investigating the toxic effects of mutant Htt in cell culture or animal models reveal mitochondrial changes including reduction of Ca2+ buffering capacity, loss of membrane potential, and decreased expression of oxidative phosphorylation (OXPHOS) enzymes. Striatal neurons may be particularly vulnerable to these defects. One hypothesis is that neurotransmission systems such as dopamine and glutamate exacerbate mitochondrial defects in the striatum. In particular, mitochondrial dysfunction facilitates impaired Ca2+ homeostasis linked to the glutamate receptor-mediated excitotoxicity. Also dopamine receptors modulate mutant Htt toxicity, at least in part through regulation of the expression of mitochondrial complex II. All these observations support the hypothesis that mitochondria, acting as "sensors" of the neurochemical environment, play a central role in striatal degeneration in HD.
Damiano
Maria
M
CEA, DSV, I2BM Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France.
Galvan
Laurie
L
Déglon
Nicole
N
Brouillet
Emmanuel
E
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D006816:Huntington Disease / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010085:Oxidative Phosphorylation
D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins