Mitochondrial structural and functional dynamics in Huntington's disease.
Huntington's disease (HD) is an autosomal, dominantly inherited neurodegenerative disorder, characterized by chorea, involuntary movements, and cognitive impairments. Tremendous progress has been made since the discovery of HD gene in 1993, in terms of developing animal models to study the disease process, unraveling the expression and function of wild-type and mutant huntingtin (Htt) proteins in the central and peripheral nervous systems, and understanding expanded CAG repeat containing mutant Htt protein interactions with CNS proteins in the disease process. HD progression has been found to involve several pathomechanisms, including expanded CAG repeat protein interaction with other CNS proteins, transcriptional dysregulation, calcium dyshomeostasis, abnormal vesicle trafficking, and defective mitochondrial bioenergetics. Recent studies have found that mutant Htt is associated with mitochondria and causes mitochondrial structural changes, decreases mitochondrial trafficking, and impairs mitochondrial dynamics in the neurons affected by HD. This article discusses recent developments in HD research, with a particular focus on intracellular and intramitochondrial calcium influx, mitochondrial DNA defects, and mitochondrial structural and functional abnormalities in HD development and progression. Further, this article outlines the current status of mitochondrial therapeutics with a special reference to Dimebon.
Reddy
P Hemachandra
PH
Neurogenetics Laboratory, Neuroscience Division, Oregon National Primate Research Center, West Campus, Oregon Health and Science University, Beaverton, OR 97006, USA. reddyh@ohsu.edu
Mao
Peizhong
P
Manczak
Maria
M
D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology*; D008928:Mitochondria / Q000473:pathology* / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D018911:Trinucleotide Repeats / Q000235:genetics
D004272:DNA, Mitochondrial; C086055:HTT protein, human; D000071058:Huntingtin Protein; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins