Mitochondrial matters in Huntington disease.
Huntington Disease (HD) is a relatively common inherited neuropathy with characteristic cognitive and behavioral features. HD usually has a late onset and often is not recognized until the third or fourth decades of life. Transmitted as an autosomal dominant trait, HD has become a prototype for understanding a group of neurogenetic disorders. As a class, HD and the others are manifestations of the expansion of a trinucleotide repeat within the gene coding or structural region. In HD expansion of the (CAG)(n) repeat in the first exon from an average of 18 (normal) to a median of 44 is the underlying molecular biologic change. In affected individuals, the mutant HD protein (Huntingtin, mHtt) thus contains an extended polyglutamine repeat. Clinical and neuropathic changes in the caudate and putamen nuclei occur relatively early with other brain regions being affected later. Mitochondrial structure, altered electron transport and increased brain lactate levels have implicated mitochondria in HD pathophysiology. There is also evidence that reduced transcription of the peroxisome proliferator-activated receptor-gamma coactivator (PGC-1 alpha) leads to altered downstream gene regulation. Further evidence for mitochondrial involvement is presented in the following reviews. Clarifying mitochondrial derangements has led to some possibilities for therapeutic intervention.
Sack
George H
GH
Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA. gsack@jhmi.edu
D004579:Electron Transport; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure
J Bioenerg Biomembr. 2010 Jun;42(3):217-26
20464463
J Bioenerg Biomembr. 2010 Jun;42(3):199-205
20556492
Cell. 2006 Oct 6;127(1):59-69
17018277
Cell. 1993 Mar 26;72(6):971-83
8458085
Nature. 1983 Nov 17-23;306(5940):234-8
6316146
N Engl J Med. 1994 May 19;330(20):1401-6
8159192
Science. 2009 Jun 5;324(5932):1327-30
19498170
Cell Metab. 2006 Nov;4(5):349-62
17055784
J Bioenerg Biomembr. 2010 Jun;42(3):207-15
20524050
Am J Hum Genet. 2009 Mar;84(3):351-66
19249009