Mutant huntingtin and mitochondrial dysfunction.

Abstract:

:Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder that gradually robs affected individuals of memory, cognitive skills and normal movements. Although 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 part in HD pathogenesis. Here, we highlight how mutant huntingtin (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, mitochondrial 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 might dictate selective vulnerability of long projection neurons, such as medium spiny neurons, which are particularly affected in HD.

journal_name

Trends Neurosci

journal_title

Trends in neurosciences

authors

Bossy-Wetzel E,Petrilli A,Knott AB

doi

10.1016/j.tins.2008.09.004

subject

Has Abstract

pub_date

2008-12-01 00:00:00

pages

609-16

issue

12

eissn

0166-2236

issn

1878-108X

pii

S0166-2236(08)00212-9

journal_volume

31

pub_type

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