ReviewMitochondrial structural and functional dynamics in Huntington's disease
Introduction
Huntington's disease (HD) is an autosomal, dominantly inherited neurodegenerative disease, characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment, and emotional disturbances (Vonsattel et al., 1985, Folstein, 1990, Bates, 2005, Lin and Beal, 2006, Montoya et al., 2006). HD occurs in 4 to 10 per 100,000 persons mainly of Caucasian origin. HD is a midlife disease with some exceptional cases of early onset as early as 2 years and of late onset in the mid 80s (Kremer, 2002). Typically, HD patients survive for about 15–20 years from the date of disease onset.
In patients with HD, selective medium spiny neuronal loss has been observed in the caudate and putamen of the striatum of basal ganglia, in pyramidal neurons of the cerebral cortex and, to lesser extent, in hippocampal and subthalamus neurons (Byers et al., 1973, Vonsattel et al., 1985, Spargo et al., 1993). The neuronal loss has been found up to 80% in patients with severe HD (Vonsattel et al., 1985). Reactive astrogliosis has also been observed in the affected brain regions of HD patients. In addition, mutant huntingtin (Htt) protein aggregates or intra-neuronal inclusions have been found in pathological sites in HD postmortem brain specimens and brain specimens from HD mouse models (Mangiarini et al., 1996, DiFiglia et al., 1997, Davies et al., 1997, Reddy et al., 1998, Reddy et al., 1999a, Reddy et al., 1999b, Schilling et al., 1999, Hodgson et al., 1999, Levine et al., 1999, Wheeler et al., 1999, Yamamoto et al., 2000).
In the last 15–20 years, tremendous progress has been made in HD research in terms of: 1) discovering HD gene, 2) understanding the expanded polyglutamine repeat containing the mutant Htt protein, 3) developing HD cell, animal models, which now include HD fly, worm, mouse, and non-human primate models (Mangiarini et al., 1996, Reddy et al., 1998, Jackson et al., 1998, Schilling et al., 1999, Kim et al., 1999, Hodgson et al., 1999, Levine et al., 1999, Yamamoto et al., 2000, Wheeler et al., 1999, Faber et al., 1999, Marsh et al., 2000, Romero et al., 2008, Lin et al., 2001, Laforet et al., 2001, Yang et al., 2008), 4) developments in decreasing the expression of the expanded polyglutamine repeat allele that has been found to damage or kill medium spiny neurons in HD patients (Harper et al., 2005, DiFiglia et al., 2007, van Bilsen et al., 2008, Zhang et al., 2009, Boudreau et al., 2009), and 5) developing therapeutics to reduce symptoms of HD in animal models and HD patients. However, the causal factors that selectively target medium spiny neurons in HD patients are still unclear. Further, the precise link between chorea and neuronal damage in HD progression is not completely understood. This article briefly reviews HD gene, the role of mutant Htt in HD progression, and mechanisms that are involved in HD pathogenesis. This article also discusses the latest developments in mitochondrial structural and functional abnormalities in relation to mutant Htt in HD pathogenesis.
Section snippets
HD gene and mutant huntingtin in HD progression
HD is a purely genetic disease unlike Alzheimer's and Parkinson's (Reddy, 2007, Reddy, 2008). In 1983, HD gene was mapped to the p arm of chromosome 16 (Gusella et al., 1983), and after 10 years of intense search with state-of-the-art molecular biology techniques and collaborations among several labs across the world, in 1993 the HD gene was identified (The Collaborative Research Group, 1993). The discovery of the HD gene (‘CAG repeat or polyglutamine repeat expansion as a mutation’) opened the
Transcriptional dysregulation and HD
Abnormal transcriptional regulation of nuclear-encoded mitochondrial genes may be involved in HD pathogenesis. Indeed, mutant Htt has been found to bind to several transcription factors, including TATA binding proteins (Huang et al., 1998, Perez et al., 1998), Sp1 (Shimohata et al., 2000), and the nuclear scaffold protein NAKAP (Sayer et al., 2005). Mutant Htt interaction may interfere with the gene expression, activity, and transcriptional regulation of HD neurons. This possibility is
Mitochondrial abnormalities and HD
Several lines of evidence suggest that abnormal mitochondrial bioenergetics is involved in HD progression.
1) Body weight loss is a major factor in the progression of HD that is reported in patients with HD and mouse models of HD (Kirkwood et al., 2001, Mahant et al., 2003, Hamilton et al., 2004, Phan et al., 2009, Aziz et al., 2008, Browne, 2008, Bossy-Wetzel et al., 2008).
2) Studies using magnetic resonance imaging of postmortem brains of HD patients revealed a progressive atrophy of the
Mutant Htt and mitochondrial trafficking abnormalities
Recently, several studies reported that mutant Htt in association with mitochondria and microtubules impair the axonal transport of mitochondria to nerve terminals (Trushina et al., 2004, Chang et al., 2006, Orr et al., 2008) (see Fig. 1). This defective mitochondrial transport ultimately impairs neural transmission, and results in synaptic damage and selective neuronal damage or loss.
In studies of HD pathogenesis, Trushina et al. (2004) investigated mutant Htt involvement in impairment of fast
Abnormal mitochondrial dynamics and HD
Mitochondrial shape and structure are maintained by 2 opposing forces: mitochondrial fusion and mitochondrial fission (Chan, 2006, Reddy, 2007, Reddy, in press). In a healthy neuron, fission and fusion mechanisms balance equally. Mitochondria alter their shape and size to move, through mitochondrial trafficking, from the cell body to the axons, dendrites, and synapses, and back to the cell body. Fission and fusion are controlled by evolutionary conserved, large GTPases belonging to the family
Mitochondrial DNA defects and HD
Age-dependent mitochondrial DNA (mtDNA) damage is hypothesized to play a role in HD pathogenesis.
Acevedo-Torres et al. (2009) investigated mitochondrial DNA defects in two HD mouse models: the chemically induced 3-nitropropionic acid model and the HD transgenic mouse model of the R6/2 strain containing 115–150 polyglutamine repeats in the HD gene. They found that mitochondrial toxin 3-NPA inhibits complex II of the ETC and causes neurodegeneration that resembles HD in the striatum of postmortem
Calcium dyshomeostasis and HD
Several lines of evidence have recently suggested that abnormal Ca2+ uptake capacity is involved in HD neurons.
Oliveira and Gonçalves (2009) investigated the buffering capacity of mitochondrial Ca2+ in cortical and striatal neuron-astrocyte co-cultures. They found that mitochondria not only in neurons but also in astrocytes from striatal origin exhibited a decrease in mitochondrial Ca2+ buffering capacity when compared with cortical counterparts. The decrease in this buffering capacity did not
Mitochondrial therapeutics, Dimebon and HD
As discussed above, recent studies suggest that mitochondrial dysfunction and calcium dyshomeostasis are key players in HD progression and pathogenesis. To reduce mitochondrial toxicity and intracellular Ca2+ influx in neurons affected by HD, drugs that protect mitochondria need to be tested, in addition to agents that boost PGC1α expression and drugs that stabilize mitochondria and inhibit mitochondrial pore opening (Reddy, 2008, Reddy and Beal, 2008).
For the last 5 years, several
Conclusions and future directions
Since the discovery of the HD gene in 1993, tremendous progress has been made in developing animal models of HD, unraveling the expression and function of wild-type and mutant Htt in the brain and peripheral tissues of HD patients, and understanding expanded polyglutamine repeats containing mutant Htt protein interactions with CNS proteins in HD progression. HD progression appears to involve several pathomechanisms, including the interaction of expanded polyglutamine repeat proteins with other
Acknowledgments
The research for this article was supported by grants from the National Institutes of Health (AG028072 and AG026051).
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