Relationship between BDNF expression in major striatal afferents,striatum morphology and motor behavior in the R6/2 mouse model of Huntington's disease

Patients with Huntington's disease (HD) and transgenic mouse models of HD show neuronal loss in the striatum as a major feature, which contributes to cognitive and motor manifestations. Reduced expression of the neurotrophin brain‐derived neurotrophic factor (BDNF) in striatal afferents may play a role in neuronal loss. How progressive loss of BDNF expression in different cortical or subcortical afferents contributes to striatal atrophy and behavioral dysfunction in HD is not known, and may best be determined in animal models. We compared age‐dependent alterations of BDNF mRNA expression in major striatal afferents from the cerebral cortex, thalamus and midbrain in the R6/2 transgenic mouse model of HD. Corresponding changes in striatal morphology were quantified using unbiased stereology. Changes in motor behavior were measured using an open field, grip strength monitor, limb clasping and a rotarod apparatus. BDNF expression in cortical limbic and midbrain striatal afferents is reduced by age 4 weeks, prior to onset of motor abnormalities. BDNF expression in motor cortex and thalamic afferents is reduced by 6 weeks, coinciding with early motor dysfunction and reduced striatum volume. BDNF loss in afferents progresses until death at 13–15 weeks, correlating with progressive striatal neuronal loss and motor abnormalities. Mutant huntingtin protein expression in R6/2 mice results in progressive loss of BDNF in both cortical and subcortical striatal afferents. BDNF loss in limbic and dopaminergic striatal inputs may contribute to cognitive/psychiatric dysfunction in HD. Subsequent BDNF loss in cortical motor and thalamic afferents may accelerate striatal degeneration, resulting in progressive involuntary movements.     

Neurodegenerative processes in Huntington's disease

Huntington''s disease (HD) is a complex and severe disorder characterized by the gradual and the progressive loss of neurons, predominantly in the striatum, which leads to the typical motor and cognitive impairments associated with this pathology. HD is caused by a highly polymorphic CAG trinucleotide repeat expansion in the exon-1 of the gene encoding for huntingtin protein. Since the first discovery of the huntingtin gene, investigations with a consistent number of in-vitro and in-vivo models have provided insights into the toxic events related to the expression of the mutant protein. In this review, we will summarize the progress made in characterizing the signaling pathways that contribute to neuronal degeneration in HD. We will highlight the age-dependent loss of proteostasis that is primarily responsible for the formation of aggregates observed in HD patients. The most promising molecular targets for the development of pharmacological interventions will also be discussed.     

Experience of experimental modelling of Huntington’s disease

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by choreic involuntary movements, decline in cognitive functions, behavioral disturbances, and progressive neuronal death affecting primarily the striatum. The fatal nature of HD makes it important to search for new effective methods of its treatment, which requires the development of experimental models of the disease. These models can be created using 3-nitropropionic acid (3-NPA), which is a neurotoxin causing typical changes in motor skills and memory impairment in animals due to induction of oxidative stress, impaired glutathione defense, and destruction of striatal cells. We modeled HD in rats by chronic daily intraperitoneal administration of 3-NPA for 17 days. Systemic administration of a low dose of 3-NPA (10 mg/kg) induced hyperactivity of animals in the open field test (including movement redundancy as a hyperkinesia analogue) and had no effect on the behavior of the animals in the X-maze test. On the contrary, rats administered with a toxic dose of 3-NPA (20 mg/kg) exhibited a significant decrease in their motor activity and a cognitive decline in behavioral tests. A histopathological analysis revealed damage and loss of neurons and a decrease in expression of dopaminergic markers (tyrosine hydroxylase and plasma membrane dopamine transporter) in the striatum. The gliotoxic effect of 3-NPA was also found in the striatum, which was confirmed by immunohistochemical staining for astrocytic proteins: GFAP, glutamine synthetase, and aquaporin-4. This HD model may be helpful for testing new experimental therapies at different stages of HD-like neurodegeneration, including therapies based on cell neurotransplantation.     

The early cellular pathology of Huntington’s disease

Huntington's disease (HD) is an inherited neurodegenerative disorder that affects about one in 10,000 individuals in North America. The genetic defect responsible for the disease is an expansion of a CAG repeat that encodes a polyglutamine tract in the expressed protein, huntingtin. The disease is characterized by involuntary movements, cognitive impairment, and emotional disturbance. Despite the widespread expression of huntingtin, the brains of HD patients show selective neuronal loss in the striatum and the deep layers of the cerebral cortex. Recent studies have shown that polyglutamine expansion causes huntingtin to aggregate, to accumulate in the nucleus, and to interact abnormally with other proteins. Several cellular and animal models for HD have revealed that intranuclear accumulation of mutant huntingtin and the formation of neuropil aggregates precede neurological symptoms and neurodegeneration. Intranuclear huntingtin may affect nuclear function and the expression of genes important for neuronal function, whereas neuropil aggregates may interfere with neuritic transport and function. These early pathological events, which occur in the absence of neurodegeneration, may contribute to the neurological symptoms of HD and ultimately lead to neuronal cell death.     

Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the R6/2 Mouse Model of HD

Huntington’s disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6/2 mouse model of HD expresses a mutant version of exon 1 HTT and develops motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Despite the vast number of studies that have been performed on this model, the association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood. In an attempt to link these factors, we have performed longitudinal assessments of behavior (rotarod, open field, passive avoidance) and of regional brain abnormalities determined through magnetic resonance imaging (MRI) (whole brain, striatum, cortex, hippocampus, corpus callosum), as well as an end-stage histological assessment. Detailed correlative analyses of these three measures were then performed. We found a gender-dependent emergence of motor impairments that was associated with an age-related loss of regional brain volumes. MRI measurements further indicated that there was no striatal atrophy, but rather a lack of striatal growth beyond 8 weeks of age. T2 relaxivity further indicated tissue-level changes within brain regions. Despite these dramatic motor and neuroanatomical abnormalities, R6/2 mice did not exhibit neuronal loss in the striatum or motor cortex, although there was a significant increase in neuronal density due to tissue atrophy. The deposition of the mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the brain. End-stage histopathological assessments were not found to be as robustly correlated with the longitudinal measures of brain atrophy or motor impairments. In conclusion, modeling pre-manifest and early progression of the disease in more slowly progressing animal models will be key to establishing which changes are causally related.     

Transgenic mice expressing mutated full-length HD cDNA: a paradigm for locomotor changes and selective neuronal loss in Huntington's disease.

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized clinically by motor and psychiatric disturbances and pathologically by neuronal loss and gliosis (reactive astrocytosis) particularly in the striatum and cerebral cortex. We have recently created HD full-length cDNA transgenic mouse models that may serve as a paradigm for HD. A more detailed characterization of these models is presented here. The transgene encoding normal huntingtin consists of 9417 bp of the huntingtin coding sequences including 16 tandem CAGs coding for polyglutamines as part of exon 1. The transgene is driven by a heterologous cytomegalovirus promoter. Five independent transgenic mouse lines were obtained using this construct. An additional six transgenic lines were obtained using full-length HD constructs that have been modified to include either 48 or 89 CAG repeat expansions. Southern blot and densitometric analyses indicated unique integration sites for the transgene in each of the lines with a copy number ranging from two to 22 copies. Widespread expression of the transgene in brain, heart, spleen, kidney, lung, liver and gonads from each line was determined by Western blot analyses. In the brain, transgene expression was found in cerebral cortex, striatum, hippocampus and cerebellum. Expression of the transgene was as much as five times the endogenous mouse huntingtin level. Phenotypically, only mice expressing 48 or 89 CAG repeats manifested progressive behavioural and motor dysfunction. Early behavioural abnormalities were characterized by trunk curling and clasping of both fore- and hindlimbs when the animals were suspended by their tails. Subsequently, these mice exhibited hyperkinetic movements, including heightened exploratory activities, unidirectional rotational behaviour, backflipping and excessive grooming that lasted for several weeks. Eventually, the animals progressed to a hypokinetic phase consisting of slowed movements and lack of response to sensory stimuli. Urine retention or incontinence was also a prominent feature of the hypokinetic phase. At the end stage of the disease process, HD48(B,D) and HD89(A-C) mice became akinetic just prior to death. Neuropathological examination of mice at various stages indicated that it was only during the hypokinetic phase and thereafter when selective neuronal loss was most apparent. Regions of neurodegeneration and loss included the striatum, cerebral cortex, thalamus and hippocampus. TUNEL staining indicated an apoptotic mode of cell death in these brain regions. Comparative neuronal counts after Nissl staining showed as much as 20% loss of small and medium neurons in the striatum in mice at the hypokinetic and akinetic stages. Reactive astrocytosis accompanied the areas of neurodegeneration and loss. Polyglutamine aggregates in the form of neuronal intranuclear inclusions and diffuse nuclear and perinuclear aggregations were found in a small percentage of neurons, including those in brain regions that are typically spared in HD. This observation suggests that polyglutamine aggregates may not be sufficient to cause neuronal loss in HD. In both behavioural and neuropathological analyses, wild-type and transgenic animals with 16 CAG repeats were indistinguishable from each other and do not exhibit the changes observed for mice carrying the 48 and 89 CAG repeat mutations. Thus, animals expressing the CAG repeat expansions appear to represent clinically analogous models for HD pathogenesis, and may also provide insights into the underlying pathophysiological mechanisms of other triplet repeat disorders.     

Cystamine treatment is neuroprotective in the YAC128 mouse model of Huntington disease

Huntington disease (HD) is an adult onset neurodegenerative disorder characterized by selective atrophy and cell loss within the striatum. There is currently no treatment that can prevent the striatal neuropathology. Transglutaminase (TG) activity is increased in HD patients, is associated with cell death, and has been suggested to contribute to striatal neuronal loss in HD. This work assesses the therapeutic potential of cystamine, an inhibitor of TG activity with additional potentially beneficial effects. Specifically, we examine the effect of cystamine on striatal neuronal loss in the YAC128 mouse model of HD. We demonstrate here for the first time that YAC128 mice show a forebrain-specific increase in TG activity compared with wild-type (WT) littermates which is decreased by oral delivery of cystamine. Treatment of symptomatic YAC128 mice with cystamine starting at 7 months prevented striatal neuronal loss. Cystamine treatment also ameliorated the striatal volume loss and striatal neuronal atrophy observed in these animals, but was unable to prevent motor dysfunction or the down-regulation of dopamine and cyclic adenosine monophsophate-regulated phosphoprotein (DARPP-32) expression in the striatum. While the exact mechanism responsible for the beneficial effects of cystamine in YAC128 mice is uncertain, our findings suggest that cystamine is neuroprotective and may be beneficial in the treatment of HD.     

Progressive depletion of complexin II in a transgenic mouse model of Huntington's disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor, emotional and cognitive dysfunction. There is no treatment or cure for this disease, and after the onset of symptoms, usually in the fourth decade of life, there is an inexorable decline to death. In many patients there is a complex deterioration of function before the onset of neuronal loss and, at least in mouse models, abnormalities in neurotransmission represent early events in the development of the disease. Here we describe the specific and progressive loss of complexin II from the brains of mice carrying the HD mutation (R6/2 line), and the later appearance of this protein in a subpopulation of neuronal intranuclear inclusions. Although the precise role of complexin II is still unclear, it is known to bind to the SNARE complex, and is therefore likely to be involved in the control of exocytosis. Our results suggest that changes in neurotransmitter release might contribute to the neuronal dysfunction seen in these mice.     

Potential role of α-synuclein in neurodegeneration: studies in a rat animal model

Neuronal protein α-synuclein (α-syn) is an essential player in the development of neurodegenerative diseases called synucleinopathies. A spontaneous autosomal recessive rat model for neurodegeneration was developed in our laboratory. These rats demonstrate progressive increases in α-syn in the brain mesencephalon followed by loss of dopaminergic terminals in the basal ganglia (BG) and motor impairments. The severity of pathology is directly related to the overexpression of α-syn and parallel decrease in dopamine (DA) level in the striatum (ST) of affected rats. The neurodegeneration in this model is characterized by the presence of perikarya and neurites Lewis bodies (LB) and diffuse marked accumulation of perikaryal α-syn in the substantia nigra (SN), brain stem (BS), and striatum (ST) along with neuronal loss. Light and ultrastructural analyses revealed that the process of neuronal degeneration is a 'dying back' type. The disease process is accompanied by gliosis and release of inflammatory cytokines. This neurodegeneration is a multisystemic disease and implicate α-syn as a major factor in the pathogenesis of this inherited autosomal recessive animal model. Decrease dopamine (DA) and overexpression of α-syn in the brain mesencephalon may provide a naturally occurring animal model for Parkinson's disease (PD) and other synucleinopathies that reproduces significant pathological, neurochemical, and behavioral features of the human disease.     

Increased Levels of Rictor Prevent Mutant Huntingtin-Induced Neuronal Degeneration

Rictor associates with mTOR to form the mTORC2 complex, which activity regulates neuronal function and survival. Neurodegenerative diseases are characterized by the presence of neuronal dysfunction and cell death in specific brain regions such as for example Huntington’s disease (HD), which is characterized by the loss of striatal projection neurons leading to motor dysfunction. Although HD is caused by the expression of mutant huntingtin, cell death occurs gradually suggesting that neurons have the capability to activate compensatory mechanisms to deal with neuronal dysfunction and later cell death. Here, we analyzed whether mTORC2 activity could be altered by the presence of mutant huntingtin. We observed that Rictor levels are specifically increased in the striatum of HD mouse models and in the putamen of HD patients. Rictor-mTOR interaction and the phosphorylation levels of Akt, one of the targets of the mTORC2 complex, were increased in the striatum of the R6/1 mouse model of HD suggesting increased mTORC2 signaling. Interestingly, acute downregulation of Rictor in striatal cells in vitro reduced mTORC2 activity, as shown by reduced levels of phospho-Akt, and increased mutant huntingtin-induced cell death. Accordingly, overexpression of Rictor increased mTORC2 activity counteracting cell death. Furthermore, normalization of endogenous Rictor levels in the striatum of R6/1 mouse worsened motor symptoms suggesting an induction of neuronal dysfunction. In conclusion, our results suggest that increased Rictor striatal levels could counteract neuronal dysfunction induced by mutant huntingtin.     

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder resulting in selective neuronal loss and dysfunction in the striatum and cortex. The molecular pathways leading to the selectivity of neuronal cell death in HD are poorly understood. Proteolytic processing of full-length mutant huntingtin (Htt) and subsequent events may play an important role in the selective neuronal cell death found in this disease. Despite the identification of Htt as a substrate for caspases, it is not known which caspase(s) cleaves Htt in vivo or whether regional expression of caspases contribute to selective neuronal cells loss. Here, we evaluate whether specific caspases are involved in cell death induced by mutant Htt and if this correlates with our recent finding that Htt is cleaved in vivo at the caspase consensus site 552. We find that caspase-2 cleaves Htt selectively at amino acid 552. Further, Htt recruits caspase-2 into an apoptosome-like complex. Binding of caspase-2 to Htt is polyglutamine repeat-length dependent, and therefore may serve as a critical initiation step in HD cell death. This hypothesis is supported by the requirement of caspase-2 for the death of mouse primary striatal cells derived from HD transgenic mice expressing full-length Htt (YAC72). Expression of catalytically inactive (dominant-negative) forms of caspase-2, caspase-7, and to some extent caspase-6, reduced the cell death of YAC72 primary striatal cells, while the catalytically inactive forms of caspase-3, -8, and -9 did not. Histological analysis of post-mortem human brain tissue and YAC72 mice revealed activation of caspases and enhanced caspase-2 immunoreactivity in medium spiny neurons of the striatum and the cortical projection neurons when compared to controls. Further, upregulation of caspase-2 correlates directly with decreased levels of brain-derived neurotrophic factor in the cortex and striatum of 3-month YAC72 transgenic mice and therefore suggests that these changes are early events in HD pathogenesis. These data support the involvement of caspase-2 in the selective neuronal cell death associated with HD in the striatum and cortex.     

Dysfunction of the ubiquitin ligase ube3a may be associated with synaptic pathophysiology in a mouse model of huntington disease

Huntington disease (HD) is a hereditary neurodegenerative disorder characterized by progressive cognitive, psychiatric, and motor symptoms. The disease is caused by abnormal expansion of CAG repeats in the gene encoding huntingtin, but how mutant huntingtin leads to early cognitive deficits in HD is poorly understood. Here, we demonstrate that the ubiquitin ligase Ube3a, which is implicated in synaptic plasticity and involved in the clearance of misfolded polyglutamine protein, is strongly recruited to the mutant huntingtin nuclear aggregates, resulting in significant loss of its functional pool in different regions of HD mouse brain. Interestingly, Arc, one of the substrates of Ube3a linked with synaptic plasticity, is also associated with nuclear aggregates, although its synaptic level is increased in the hippocampus and cortex of HD mouse brain. Different regions of HD mouse brain also exhibit decreased levels of AMPA receptors and various pre- and postsynaptic proteins, which could be due to the partial loss of function of Ube3a. Transient expression of mutant huntingtin in mouse primary cortical neurons further demonstrates recruitment of Ube3a into mutant huntingtin aggregates, increased accumulation of Arc, and decreased numbers of GluR1 puncta in the neuronal processes. Altogether, our results suggest that the loss of function of Ube3a might be associated with the synaptic abnormalities observed in HD.     

CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in exon 1 of the Huntingtin (Htt) gene. We show herein that in an HD transgenic mouse model (R6/2), daily administration of CGS21680 (CGS), an A(2A) adenosine receptor (A(2A)-R)-selective agonist, delayed the progressive deterioration of motor performance and prevented a reduction in brain weight. 3D-microMRI analysis revealed that CGS reversed the enlarged ventricle-to-brain ratio of R6/2 mice, with particular improvements in the left and right ventricles. (1)H-MRS showed that CGS significantly reduced the increased choline levels in the striatum. Immunohistochemical analyses further demonstrated that CGS reduced the size of ubiquitin-positive neuronal intranuclear inclusions (NIIs) in the striatum of R6/2 mice and ameliorated mutant Htt aggregation in a striatal progenitor cell line overexpressing mutant Htt with expanded polyQ. Moreover, chronic CGS treatment normalized the elevated blood glucose levels and reduced the overactivation of a major metabolic sensor [5'AMP-activated protein kinase (AMPK)] in the striatum of R6/2 mice. Since AMPK is a master switch for energy metabolism, modulation of energy dysfunction caused by the mutant Htt might contribute to the beneficial effects of CGS. Collectively, CGS is a potential drug candidate for the treatment of HD.     

Mitochondria in Huntington's disease

Huntington's disease (HD) is an inherited progressive neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits and psychiatric disturbances. The disease is caused by an abnormal expansion of a CAG repeat located in exon 1 of the gene encoding the huntingtin protein (Htt) that confers a toxic function to the protein. The most striking neuropathological change in HD is the preferential loss of medium spiny GABAergic neurons in the striatum. The mechanisms underlying striatal vulnerability in HD are unknown, but compelling evidence suggests that mitochondrial defects may play a central role. Here we review recent findings supporting this hypothesis. Studies investigating the toxic effects of mutant Htt in cell culture or animal models reveal mitochondrial changes including reduction of Ca²⁺ buffering capacity, loss of membrane potential, and decreased expression of oxidative phosphorylation (OXPHOS) enzymes. Striatal neurons may be particularly vulnerable to these defects. One hypothesis is that neurotransmission systems such as dopamine and glutamate exacerbate mitochondrial defects in the striatum. In particular, mitochondrial dysfunction facilitates impaired Ca²⁺ homeostasis linked to the glutamate receptor-mediated excitotoxicity. Also dopamine receptors modulate mutant Htt toxicity, at least in part through regulation of the expression of mitochondrial complex II. All these observations support the hypothesis that mitochondria, acting as “sensors” of the neurochemical environment, play a central role in striatal degeneration in HD.     

Striatal Synaptic Dysfunction and Hippocampal Plasticity Deficits in the Hu97/18 Mouse Model of Huntington Disease

Huntington disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the gene (HTT) encoding the huntingtin protein (HTT). This mutation leads to multiple cellular and synaptic alterations that are mimicked in many current HD animal models. However, the most commonly used, well-characterized HD models do not accurately reproduce the genetics of human disease. Recently, a new ‘humanized’ mouse model, termed Hu97/18, has been developed that genetically recapitulates human HD, including two human HTT alleles, no mouse Hdh alleles and heterozygosity of the HD mutation. Previously, behavioral and neuropathological testing in Hu97/18 mice revealed many features of HD, yet no electrophysiological measures were employed to investigate possible synaptic alterations. Here, we describe electrophysiological changes in the striatum and hippocampus of the Hu97/18 mice. At 9 months of age, a stage when cognitive deficits are fully developed and motor dysfunction is also evident, Hu97/18 striatal spiny projection neurons (SPNs) exhibited small changes in membrane properties and lower amplitude and frequency of spontaneous excitatory postsynaptic currents (sEPSCs); however, release probability from presynaptic terminals was unaltered. Strikingly, these mice also exhibited a profound deficiency in long-term potentiation (LTP) at CA3-to-CA1 synapses. In contrast, at 6 months of age we found only subtle alterations in SPN synaptic transmission, while 3-month old animals did not display any electrophysiologically detectable changes in the striatum and CA1 LTP was intact. Together, these data reveal robust, progressive deficits in synaptic function and plasticity in Hu97/18 mice, consistent with previously reported behavioral abnormalities, and suggest an optimal age (9 months) for future electrophysiological assessment in preclinical studies of HD.     

Double-strand RNA dependent protein kinase (PKR) is involved in the extrastriatal degeneration in Parkinson's disease and Huntington's disease

Double-strand RNA dependent protein kinase (PKR) plays an important role in control of cell death. We previously reported that activation of PKR is associated with hippocampal neuronal loss in Alzheimer's disease (AD). Recent studies have reported that Parkinson's (PD) and Huntington's (HD) disease brains displayed progressive hippocampal neuronal loss in extrastriatal degeneration. However, association between PKR and hippocampal neuronal loss in PD and HD brains is not known. In this report, brain tissues from patients with PD and HD displayed strong induction of phosphorylated-PKR (p-PKR) in hippocampal neurons. Immunoblotting analysis also demonstrated that levels of nuclear p-PKR in the hippocampus affected by these diseases were increased compared with age-matched disease controls. These results suggest that a close association exists between PKR and extrastriatal degeneration in PD and HD pathology.     

Cellular and molecular mechanisms implicated in pathogenesis of selective neurodegeneration in Huntington’s disease

Huntington??s disease (HD) is one of the most common dominantly-inherited neurodegenerative disorders and is caused by a CAG repeat expansion in the huntingtin gene. HD is characterized by selective degeneration of subpopulations of neurons in the brain, however the precise underlying mechanisms how a ubiquitously expressed disease protein could target specific types of neurons for degeneration remains a critical, yet unanswered question for HD and other major neurodegenerative disorders. In this review, we describe the expanding view of selective neuronal vulnerability in HD, based on recent neuropathological and neuroimaging studies. We will also summarize the systematic effort to define the cell types in which mutant Huntingtin expression is critical for pathogenesis of vulnerable neurons in the striatum and cortex. Finally, we will describe selected, emerging molecular mechanisms that are implicated in selective disease processes in HD. Together, the field has begun to appreciate the distinct molecular pathogenic roles of mutant huntingtin in different cell types that may contribute to the selective neuronal vulnerability, with dissection of such mechanisms likely to yield novel molecular targets for HD therapy.     

The Energetics of Huntington's Disease

Huntington's disease (HD) is a hereditary neurodegenerative disorder that gradually robs sufferers of the ability to control movements and induces psychological and cognitive impairments. This devastating, lethal disease is one of several neurological disorders caused by trinucleotide expansions in affected genes, including spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, and spinal bulbar muscular atrophy. HD symptoms are associated with region-specific neuronal loss within the central nervous system, but to date the mechanism of this selective cell death remains unknown. Strong evidence from studies in humans and animal models suggests the involvement of energy metabolism defects, which may contribute to excitotoxic processes, oxidative dmage, and altered gene regulation. The development of transgenic mouse models expressing the human HD mutation has provided novel opportunities to explore events underlying selective neuronal death in HD, which has hitherto been impossible in humans. Here we discuss how animal models are redefining the role of energy metabolism in HD etiology.