Pathophysiology Of Huntington's Disease Research Articles

Ubiquitin-specific protease-14 reduces cellular aggregates and protects against mutant huntingtin-induced cell degeneration: involvement of the proteasome and ER stress-activated kinase IRE1α.

Huntington's disease (HD) is an autosomal inherited neurological disease caused by a CAG-repeat expansion in the first exon of huntingtin gene encoding for the huntingtin protein (Htt). In HD, there is an accumulation of intracellular aggregates of mutant Htt that negatively influence cellular functions. The aggregates contain ubiquitin, and part of the HD pathophysiology could result from an imbalance in cellular ubiquitin levels. Deubiquitinating enzymes are important for replenishing the ubiquitin pool, but less is known about their roles in brain diseases. We show here that overexpression of the ubiquitin-specific protease-14 (Usp14) reduces cellular aggregates in mutant Htt-expressing cells mainly via the ubiquitin proteasome system. We also observed that the serine-threonine kinase IRE1 involved in endoplasmic reticulum (ER) stress responses is activated in mutant Htt-expressing cells in culture as well as in the striatum of mutant Htt transgenic (BACHD) mice. Usp14 interacted with IRE1 in control cells but less in mutant Htt-expressing cells. Overexpression of Usp14 in turn was able to inhibit phosphorylation of IRE1α in mutant Htt-overexpressing cells and to protect against cell degeneration and caspase-3 activation. These results show that ER stress-mediated IRE1 activation is part of mutant Htt toxicity and that this is counteracted by Usp14 expression. Usp14 effectively reduced cellular aggregates and counteracted cell degeneration indicating an important role of this protein in mutant Htt-induced cell toxicity.

Cystathionine γ-lyase deficiency mediates neurodegeneration in Huntington’s disease

Huntington's disease is an autosomal dominant disease associated with a mutation in the gene encoding huntingtin (Htt) leading to expanded polyglutamine repeats of mutant Htt (mHtt) that elicit oxidative stress, neurotoxicity, and motor and behavioural changes. Huntington's disease is characterized by highly selective and profound damage to the corpus striatum, which regulates motor function. Striatal selectivity of Huntington's disease may reflect the striatally selective small G protein Rhes binding to mHtt and enhancing its neurotoxicity. Specific molecular mechanisms by which mHtt elicits neurodegeneration have been hard to determine. Here we show a major depletion of cystathionine γ-lyase (CSE), the biosynthetic enzyme for cysteine, in Huntington's disease tissues, which may mediate Huntington's disease pathophysiology. The defect occurs at the transcriptional level and seems to reflect influences of mHtt on specificity protein 1, a transcriptional activator for CSE. Consistent with the notion of loss of CSE as a pathogenic mechanism, supplementation with cysteine reverses abnormalities in cultures of Huntington's disease tissues and in intact mouse models of Huntington's disease, suggesting therapeutic potential.

Identification of a post-translationally myristoylated autophagy-inducing domain released by caspase cleavage of Huntingtin

Huntington disease (HD) is a debilitating neurodegenerative disease characterized by the loss of motor control and cognitive ability that ultimately leads to death. It is caused by the expansion of a polyglutamine tract in the huntingtin (HTT) protein, which leads to aggregation of the protein and eventually cellular death. Both the wild-type and mutant form of the protein are highly regulated by post-translational modifications including proteolysis, palmitoylation and phosphorylation. We now demonstrate the existence of a new post-translational modification of HTT: the addition of the 14 carbon fatty acid myristate to a glycine residue exposed on a caspase-3-cleaved fragment (post-translational myristoylation) and that myristoylation of this fragment is altered in a physiologically relevant model of mutant HTT. Myristoylated HTT553-585-EGFP, but not its non-myristoylated variant, initially localized to the ER, induced the formation of autophagosomes and accumulated in abnormally large autophagolysosomal/lysosomal structures in a variety of cell types, including neuronal cell lines under nutrient-rich conditions. Our results suggest that accumulation of myristoylated HTT553-586 in cells may alter the rate of production of autophagosomes and/or their clearance through the heterotypic autophagosomal/lysosomal fusion process. Overall, our novel observations establish a role for the post-translational myristoylation of a caspase-3-cleaved fragment of HTT, highly similar to the Barkor/ATG14L autophagosome-targeting sequence domain thought to sense, maintain and/or promote membrane curvature in the regulation of autophagy. Abnormal processing or production of this myristoylated HTT fragment might be involved in the pathophysiology of HD.

Preclinical and clinical investigations of mood stabilizers for Huntington's disease: what have we learned?

Huntington's disease (HD) is a lethal, autosomal dominant neurodegenerative disorder caused by CAG repeat expansions at exon 1 of the huntingtin (Htt) gene, which encodes for a mutant huntingtin protein (mHtt). Prominent symptoms of HD include motor dysfunction, characterized by chorea; psychiatric disturbances such as mood and personality changes; and cognitive decline that may lead to dementia. Pathologically multiple complex processes and pathways are involved in the development of HD, including selective loss of neurons in the striatum and cortex, dysregulation of cellular autophagy, mitochondrial dysfunction, decreased neurotrophic and growth factor levels, and aberrant regulation of gene expression and epigenetic patterns. No cure for HD presently exists, nor are there drugs that can halt the progression of this devastating disease. Therefore, the need to discover neuroprotective modalities to combat HD is critical. In basic and preclinical studies using cellular and animal HD models, the mood stabilizers lithium and valproic acid (VPA) have shown multiple beneficial effects, including behavioral and motor improvement, enhanced neuroprotection, and lifespan extension. Recent studies in transgenic HD mice support the notion that combined lithium/VPA treatment is more effective than treatment with either drug alone. In humans, several clinical studies of HD patients found that lithium treatment improved mood, and that VPA treatment both stabilized mood and moderately reduced chorea. In contrast, other studies observed that the hallmark features of HD were unaffected by treatment with either lithium or VPA. The current review discusses preclinical and clinical investigations of the beneficial effects of lithium and VPA on HD pathophysiology.

Region-specific pro-survival signaling and global neuronal protection by wild-type Huntingtin.

Huntington's disease (HD), caused by polyglutamine expansion in huntingtin (Htt), results in severe neurodegeneration in the striatum, and to a lesser extent, cortex and hippocampus. In contrast, non-expanded huntingtin (wildtype, wtHtt) enhances pro-survival trophic factor BDNF expression and protects striatal neurons from excitotoxicity, a mechanism thought to contribute to HD pathophysiology; however, it is unknown whether these effects of wtHtt extend to other brain areas. Test wtHtt's role in pro-survival signaling and neuroprotection in striatum, cortex and hippocampus. Levels of nuclear phosphorylated cAMP response element-binding protein (pCREB), a regulator of pro-survival gene transcription, and resistance to NMDA-induced apoptosis in primary neuronal cultures - hippocampal and corticostriatal co-culture -were assessed using immunocytochemistry and excitotoxicity assays, respectively. Cultures from wild-type FVB/N (WT) mice were compared with those from YAC18 mice on an FVB/N background, expressing both human, full-length wtHtt and normal levels of murine Htt. Basal pCREB was higher in YAC18 striatal but not cortical or hippocampal neurons; however, all three types showed decreased apoptosis in YAC18 vs. WT cultures. Increased striatal neuronal pCREB required wtHtt overexpression in both cortical and striatal neurons. Reduced response to exogenous BDNF, or its soluble scavenger TrkB-Fc, suggested enhanced BDNF signaling contributes to increased YAC18 striatal pCREB. Basal pro-survival signaling does not predict neuronal vulnerability to apoptosis in our culture system, since wtHtt overexpression elevates basal pCREB selectively in striatal neurons but is more globally neuroprotective. These results extend knowledge of the physiological roles of huntingtin, facilitating development of HD therapeutics.

β Oscillation during Slow Wave Sleep and Rapid Eye Movement Sleep in the Electroencephalogram of a Transgenic Mouse Model of Huntington’s Disease

Study objectivesTo search for early abnormalities in electroencephalogram (EEG) during sleep which may precede motor symptoms in a transgenic mouse model of hereditary neurodegenerative Huntington’s disease (HD).DesignIn the R6/1 transgenic mouse model of HD, rhythmic brain activity in EEG recordings was monitored longitudinally and across vigilance states through the onset and progression of disease.Measurements and resultsMice with chronic electrode implants were recorded monthly over wake-sleep cycles (4 hours), beginning at 9–11 weeks (presymptomatic period) through 6–7 months (symptomatic period). Recording data revealed a unique β rhythm (20–35 Hz), present only in R6/1 transgenic mice, which evolves in close parallel with the disease. In addition, there was an unusual relationship between this β oscillation and vigilance states: while nearly absent during the active waking state, the β oscillation appeared with drowsiness and during slow wave sleep (SWS) and, interestingly, strengthened rather than dissipating when the brain returned to an activated state during rapid eye movement (REM) sleep.ConclusionsIn addition to providing a new in vivo biomarker and insight into Huntington's disease pathophysiology, this serendipitous observation opens a window onto the rarely explored neurophysiology of the cortico-basal ganglia circuit during SWS and REM sleep.

Hyperactivity and cortical disinhibition in mice with restricted expression of mutant huntingtin to parvalbumin-positive cells

Recent evidence suggests that interneurons are involved in the pathophysiology of Huntington Disease (HD). Abnormalities in the function of interneurons expressing the calcium buffer parvalbumin (PV) have been observed in multiple mouse models of HD, although it is not clear how PV-positive interneuron dysfunction contributes to behavioral and synaptic deficits. Here, we use the cre-lox system to drive expression of mutant huntingtin (mthtt) in parvalbumin (PV)-positive neurons and find that mutant mice exhibit diffuse mthtt immunoreactivity in PV-rich areas at 10months of age and mthtt aggregates in PV-positive processes at 24months of age. At midlife, mutant mice are hyperactive and display impaired GABA release in the motor cortex, characterized by reduced miniature inhibitory events and severely blunted responses to gamma frequency stimulation, without a loss of PV-positive interneurons. In contrast, 24month-old mutant mice show normalized behavior and responses to gamma frequency stimulation, possibly due to compensatory changes in pyramidal neurons or the formation of inclusions with age. These data indicate that mthtt expression in PV-positive neurons is sufficient to drive a hyperactive phenotype and suggest that mthtt-mediated dysfunction in PV-positive neuronal populations could be a key factor in the hyperkinetic behavior observed in HD. Further clarification of the roles for specific PV-positive populations in this phenotype is warranted to definitively identify cellular targets for intervention.

Loss of caveolin-1 expression in knock-in mouse model of Huntington's disease suppresses pathophysiology in vivo

Loss of cholesterol homeostasis and altered vesicle trafficking have been detected in Huntington's disease (HD) cellular and animal models, yet the role of these dysfunctions in pathophysiology of HD is unknown. We demonstrate here that defects in caveolar-related cholesterol trafficking directly contribute to the mechanism of HD in vivo. We generated new mouse models that express mutant Huntington's protein (mhtt), but have partial or total loss of caveolin-1 (Cav1) expression. Fluorescence resonance energy transfer dequenching confirms a direct interaction between mhtt and Cav1. Mhtt-expressing neurons exhibited cholesterol accumulation and suppressed caveolar-related post-Golgi trafficking from endoplasmic reticulum/Golgi to plasma membrane. Loss or reduction of Cav1 expression in a knock-in HD mouse model rescues the cholesterol phenotype in neurons and significantly delays the onset of motor decline and development of neuronal inclusions. We propose that aberrant interaction between Cav1 and mhtt leads to altered cholesterol homeostasis and plays a direct causative role in the onset of HD pathophysiology in vivo.

Androgen Function in the Pathophysiology and Treatment of Male Huntington’s Disease Patients

Low concentrations of circulating testosterone have been associated with dementia manifesting with advancing age and in neurodegenerative conditions. Huntington's disease (HD) is a dominantly inherited neurodegenerative disease with an invariably fatal outcome. Severe motor symptoms, psychosis and dementia are symptomatic hallmarks of the progression of HD that result from the dysfunction and death of neocortical and basal ganglia neurones. Treatments are directed toward manifest symptoms, although they are largely ineffectual in slowing or preventing disease progression. Emerging data have identified hypothamic pathologies in HD that result in endocrine disturbances. Clinically defined primary or secondary hypogonadism elicit low circulating testosterone concentrations and have been linked to the development of Alzheimer's disease in men. Examining similar neuroendocrine dysfunction in HD including the nature of manifest hypogonadism in male patients could allow an elucidation of the complex pathophysiology of HD and provide an impetus for hitherto untested testosterone replacement therapy.

C02 β-catenin expression in minipigs transgenic for human mutated huntingtin

Background β-catenin is a key component of Wnt signalling pathway which controls brain development and neurogenesis of the adult brain. Within a cell, β-catenin is continuously synthesised and its level is strictly regulated by phosphorylation and subsequent degradation via ubiquitin-proteasome system. Recently, the accumulation of β-catenin has been associated with Huntington disease as a consequence of the impaired degradation caused by mutated huntingtin. Aims Our study is aimed at monitoring β-catenin level in minipigs transgenic for the N-terminal part of human mutated huntingtin, the model developed in our institute. Methods Using Western blot and specific antibodies, transgenic animals and their siblings of the same age and the identical genetic background were examined for the expression of β-catenin. Furthermore, phosphorylation of β-catenin was monitored applying the method of phosphoprotein isolation. Finally, β-catenin was isolated by immunoprecipitation and subjected to mass-spectrometric analysis. Results Two forms of β-catenin with minimal variance in molecular weight were detected in all samples from transgenic and wild-type pigs. Although there were no significant differences in β-catenin of the lower molecular weight, a noticeable decrease of heavier form was observed in transgenic animals. More interestingly, β-catenin of lower molecular weight was substantially phosphorylated suggesting that such modification is not responsible for the presence of heavier β-catenin in control animals. In order to reveal the differences among two observed forms of β-catenin, immunoprecipitation followed by mass spectrometry was performed and results will be discussed. Conclusion Our results demonstrate the presence of two distinct forms of β-catenin and indicate that a specific form of the protein is almost absent in transgenic animals. We hope that in depth investigation of this protein will extend our knowledge about the pathophysiology of Huntington disease.

Developmental alterations in motor coordination and medium spiny neuron markers in mice lacking pgc-1α.

Accumulating evidence implicates the transcriptional coactivator peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) in the pathophysiology of Huntington Disease (HD). Adult PGC-1α −/− mice exhibit striatal neurodegeneration, and reductions in the expression of PGC-1α have been observed in striatum and muscle of HD patients as well as in animal models of the disease. However, it is unknown whether decreased expression of PGC-1α alone is sufficient to lead to the motor phenotype and striatal pathology characteristic of HD. For the first time, we show that young PGC-1α −/− mice exhibit severe rotarod deficits, decreased rearing behavior, and increased occurrence of tremor in addition to the previously described hindlimb clasping. Motor impairment and striatal vacuolation are apparent in PGC-1α −/− mice by four weeks of age and do not improve or decline by twelve weeks of age. The behavioral and pathological phenotype of PGC-1α −/− mice can be completely recapitulated by conditional nervous system deletion of PGC-1α, indicating that peripheral effects are not responsible for the observed abnormalities. Evaluation of the transcriptional profile of PGC-1α −/− striatal neuron populations and comparison to striatal neuron profiles of R6/2 HD mice revealed that PGC-1α deficiency alone is not sufficient to cause the transcriptional changes observed in this HD mouse model. In contrast to R6/2 HD mice, PGC-1α −/− mice show increases in the expression of medium spiny neuron (MSN) markers with age, suggesting that the observed behavioral and structural abnormalities are not primarily due to MSN loss, the defining pathological feature of HD. These results indicate that PGC-1α is required for the proper development of motor circuitry and transcriptional homeostasis in MSNs and that developmental disruption of PGC-1α leads to long-term alterations in motor functioning.

Altered diffusion tensor imaging measurements in aged transgenic Huntington disease rats

Rodent models of Huntington disease (HD) are valuable tools for investigating HD pathophysiology and evaluating new therapeutic approaches. Non-invasive characterization of HD-related phenotype changes is important for monitoring progression of pathological processes and possible effects of interventions. The first transgenic rat model for HD exhibits progressive late-onset affective, cognitive, and motor impairments, as well as neuropathological features reflecting observations from HD patients. In this report, we contribute to the anatomical phenotyping of this model by comparing high-resolution ex vivo DTI measurements obtained in aged transgenic HD rats and wild-type controls. By region of interest analysis supplemented by voxel-based statistics, we find little evidence of atrophy in basal ganglia regions, but demonstrate altered DTI measurements in the dorsal and ventral striatum, globus pallidus, entopeduncular nucleus, substantia nigra, and hippocampus. These changes are largely compatible with DTI findings in preclinical and clinical HD patients. We confirm earlier reports that HD rats express a moderate neuropathological phenotype, and provide evidence of altered DTI measures in specific HD-related brain regions, in the absence of pronounced morphometric changes.

Protein oxidation in Huntington disease

Huntington disease (HD) is an inherited neurodegenerative disorder caused by expansion of CAG repeats in the huntingtin gene, affecting initially the striatum and progressively the cortex. Oxidative stress, and consequent protein oxidation, has been described as important to disease progression. This review focuses on recent advances in the field, with a particular emphasis on the identified target proteins and the role that their oxidation has or might have in the pathophysiology of HD. Oxidation and the resulting inactivation and/or degradation of important proteins can explain the impairment of several metabolic pathways in HD. Oxidation of enzymes involved in ATP synthesis can account for the energy deficiency observed. Impairment of protein folding and degradation can be due to oxidation of several heat shock proteins and Valosin-containing protein. Oxidation of two enzymes involved in the vitamin B6 metabolism could result in decreased availability of pyridoxal phosphate, which is a necessary cofactor in transaminations, the kynurenine pathway and the synthesis of glutathione, GABA, dopamine and serotonin, all of which have a key role in HD pathology. In addition, protein oxidation often contributes to oxidative stress, aggravating the molecular damage inside the cell.

Inositol Hexakisphosphate Kinases Induce Cell Death in Huntington Disease

Inositol pyrophosphate diphosphoinositol pentakisphosphate is ubiquitously present in mammalian cells and contains highly energetic pyrophosphate bonds. We have previously reported that inositol hexakisphosphate kinase type 2 (InsP(6)K2), which converts inositol hexakisphosphate to inositol pyrophosphate diphosphoinositol pentakisphosphate, mediates apoptotic cell death via its translocation from the nucleus to the cytoplasm. Here, we report that InsP(6)K2 is localized mainly in the cytoplasm of lymphoblast cells from patients with Huntington disease (HD), whereas this enzyme is localized in the nucleus in control lymphoblast cells. The large number of autophagosomes detected in HD lymphoblast cells is consistent with the down-regulation of Akt in response to InsP(6)K2 activation. Consistent with these observations, the overexpression of InsP(6)Ks leads to the depletion of Akt phosphorylation and the induction of cell death. These results suggest that InsP(6)K2 activation is associated with the pathogenesis of HD.

Could successful (mitochondrial) networking help prevent Huntington's disease?

Polyglutamine expansions in huntingtin (Htt) are known to cause the profound neurodegenerative disorder, Huntington's disease (HD). Mitochondrial dysfunction has long been implicated in the pathophysiology of HD, but the underlying mechanism remains obscure. An article by Costa et al in this months edition describes a smooth mechanistic cascade from the well-accepted upstream event that mutant Htt is associated with Ca2+ handling abnormalities, through to apoptotic neuronal death. The proposed cascade implicates calcineurin, activated by abnormal Ca2+ levels, in the dephosphorylation of dynamin-1-like protein (Drp1), increasing its association with mitochondria and promoting fission, cristae disruption, cytochrome c release and apoptosis (Fig 1). Together with the recent reports of increased mitochondrial fission in striatal neurons from HD patients, the article by Costa et al provides a compelling case for the role of abnormal mitochondrial networking in HD pathogenesis.

Attenuation of proinflammatory cytokines and apoptotic process by verapamil and diltiazem against quinolinic acid induced Huntington like alterations in rats

Huntington disease is a neurodegenerative disease with complex pathophysiology. Recently, role of neuroinflammation and interplay between various other cellular cascades have been suggested to be involved in pathophysiology of Huntington disease. Involvement of calcium overload mediated oxidative damage and excitotoxicity have been suggested to play a central role in quinolinic acid induced Huntington like symptoms. The present study has been carried out to investigate the neuroprotective effect of calcium channel blockers (verapamil and diltiazem) against quinolinic acid induced dysfunction in motor, biochemical and neuroinflammatory signaling in rats. Intrastriatal quinolinic acid administration leads to significant motor [locomotor (72% reduction), rotarod (55% reduction), balance beam walk performance] dysfunction coupled with the marked oxidative damage and increased neuroinflammatory markers [TNF-α (140%), IL-6 (115%), caspase-3(75%)] levels in striatum as compared to the sham treatment. Verapamil (10 and 20mg/kg), diltiazem (10 and 20mg/kg) drug treatment for 21days resulted in a significant improvement in the motor function (improvement in locomotor activity, rotarod and balance beam walk performance). Further, verapamil (10 and 20mg/kg), diltiazem (10 and 20mg/kg) treatment significantly attenuated oxidative damage, level of proinflammatory mediators (TNF-α IL-6 and caspase-3) in quinolinic acid treated animals. Results of the present study demonstrate that protective effect of these calcium channel blockers (verapamil, diltiazem) might be due to their inhibitory action on different neuroinflammatory pathways against quinolinic acid induced Huntington disease like symptoms in rats.

Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease

Caused by a polyglutamine expansion in the huntingtin protein, Huntington's disease leads to striatal degeneration via the transcriptional dysregulation of a number of genes, including those involved in mitochondrial biogenesis. Here we show that transglutaminase 2, which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes; transglutaminase 2 interacts directly with histone H3 in the nucleus. In a cellular model of HD, transglutaminase inhibition de-repressed two established regulators of mitochondrial function, PGC-1α and cytochrome c and reversed susceptibility of human HD cells to the mitochondrial toxin, 3-nitroproprionic acid; however, protection mediated by transglutaminase inhibition was not associated with improved mitochondrial bioenergetics. A gene microarray analysis indicated that transglutaminase inhibition normalized expression of not only mitochondrial genes but also 40% of genes that are dysregulated in HD striatal neurons, including chaperone and histone genes. Moreover, transglutaminase inhibition attenuated degeneration in a Drosophila model of HD and protected mouse HD striatal neurons from excitotoxicity. Altogether these findings demonstrate that selective TG inhibition broadly corrects transcriptional dysregulation in HD and defines a novel HDAC-independent epigenetic strategy for treating neurodegeneration.

Neuroinflammation in Huntington’s disease

Huntington's disease (HD) is a monogenic neurodegenerative disease characterized by abnormal motor movements, personality changes and early death. In contrast to other neurodegenerative diseases, very little is known about the role of neuroinflammation in HD. While the current data clearly demonstrate the existence of inflammatory processes in HD pathophysiology, the question of whether neuroinflammation is purely reactive or might actively participate in disease pathogenesis is currently a matter of ongoing research and debate. This review will try to shed some light on the current state of research in this area and provide an outlook on potential future developments.

Mitochondrial matters in Huntington disease

Huntington Disease (HD) is a relatively common inherited neuropathy with characteristic cognitive and behavioral features. HD usually has a late onset and often is not recognized until the third or fourth decades of life. Transmitted as an autosomal dominant trait, HD has become a prototype for understanding a group of neurogenetic disorders. As a class, HD and the others are manifestations of the expansion of a trinucleotide repeat within the gene coding or structural region. In HD expansion of the (CAG)(n) repeat in the first exon from an average of 18 (normal) to a median of 44 is the underlying molecular biologic change. In affected individuals, the mutant HD protein (Huntingtin, mHtt) thus contains an extended polyglutamine repeat. Clinical and neuropathic changes in the caudate and putamen nuclei occur relatively early with other brain regions being affected later. Mitochondrial structure, altered electron transport and increased brain lactate levels have implicated mitochondria in HD pathophysiology. There is also evidence that reduced transcription of the peroxisome proliferator-activated receptor-gamma coactivator (PGC-1 alpha) leads to altered downstream gene regulation. Further evidence for mitochondrial involvement is presented in the following reviews. Clarifying mitochondrial derangements has led to some possibilities for therapeutic intervention.

Altered cholesterol and fatty acid metabolism in Huntington disease

Huntington disease is an autosomal dominant neurodegenerative disorder characterized by behavioral abnormalities, cognitive decline, and involuntary movements that lead to a progressive decline in functional capacity, independence, and ultimately death. The pathophysiology of Huntington disease is linked to an expanded trinucleotide repeat of cytosine-adenine-guanine (CAG) in the IT-15 gene on chromosome 4. There is no disease-modifying treatment for Huntington disease, and novel pathophysiological insights and therapeutic strategies are needed. Lipids are vital to the health of the central nervous system, and research in animals and humans has revealed that cholesterol metabolism is disrupted in Huntington disease. This lipid dysregulation has been linked to specific actions of the mutant huntingtin on sterol regulatory element binding proteins. This results in lower cholesterol levels in affected areas of the brain with evidence that this depletion is pathologic. Huntington disease is also associated with a pattern of insulin resistance characterized by a catabolic state resulting in weight loss and a lower body mass index than individuals without Huntington disease. Insulin resistance appears to act as a metabolic stressor attending disease progression. The fish-derived omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have been examined in clinical trials of Huntington disease patients. Drugs that combat the dysregulated lipid milieu in Huntington disease may help treat this perplexing and catastrophic genetic disease.