Mutant huntingtin and mitochondrial dysfunction (original) (raw)

2008, Trends in Neurosciences

Huntington's disease (HD) is a fatal inherited neurodegenerative disorder that gradually robs affected individuals of memory, cognitive skills, and normal movements. While research has identified a single faulty gene, the huntingtin gene, as the cause of the disease, a cure remains elusive. Strong evidence indicates that mitochondrial impairment plays a key role in HD pathogenesis. Here, we highlight how mtHtt might cause mitochondrial dysfunction by either perturbing transcription of nuclear-encoded mitochondrial proteins or by direct interaction with the organelle and modulation of respiration, membrane potential and Ca 2+ buffering. In addition, we propose that mtHtt might convey its neurotoxicity by evoking defects in mitochondrial dynamics, organelle trafficking and fission and fusion, which in turn might result in bioenergetic failure and HD-linked neuronal dysfunction and cell death. Finally, we speculate how mitochondria may dictate selective vulnerability of long projection neurons, such as medium spiny neurons, which are particularly affected in HD.

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