YAC128 Mouse Model Of Huntington's Disease Research Articles

Impaired development of cortico-striatal synaptic connectivity in a cell culture model of Huntington's disease

Huntington's disease (HD) is a genetically inherited neurodegenerative disease caused by a mutation in the gene encoding the huntingtin protein. This mutation results in progressive cell death that is particularly striking in the striatum. Recent evidence indicates that early HD is initially a disease of the synapse, in which subtle alterations in synaptic neurotransmission, particularly at the cortico-striatal (C-S) synapse, can be detected well in advance of cell death. Here, we used a cell culture model in which striatal neurons are co-cultured with cortical neurons, and monitored the development of C-S connectivity up to 21days in vitro (DIV) in cells cultured from either the YAC128 mouse model of HD or the background strain, FVB/N (wild-type; WT) mice. Our data demonstrate that while C-S connectivity in WT co-cultures develops rapidly and continuously from DIV 7 to 21, YAC128 C-S connectivity shows no significant growth from DIV 14 onward. Morphological and electrophysiological data suggest that a combination of pre- and postsynaptic mechanisms contribute to this effect, including a reduction in both the postsynaptic dendritic arborization and the size and replenishment rate of the presynaptic readily releasable pool of excitatory vesicles. Moreover, a chimeric culture strategy confirmed that the most robust impairment in C-S connectivity was only observed when mutant huntingtin was expressed both pre- and postsynaptically. In all, our data demonstrate a progressive HD synaptic phenotype in this co-culture system that may be exploited as a platform for identifying promising therapeutic strategies to prevent early HD-associated synaptopathy.

Protection by dietary restriction in the YAC128 mouse model of Huntington's disease: Relation to genes regulating histone acetylation and HTT

Huntington's disease (HD) is a fatal neurodegenerative disease characterized by metabolic, cognitive, and motor deficits. HD is caused by an expanded CAG repeat in the first exon of the HTT gene, resulting in an expanded polyglutamine section. Dietary restriction (DR) increases lifespan and ameliorates age-related pathologies, including in a model of HD, but the mechanisms mediating these protective effects are unknown. We report metabolic and behavioral effects of DR in the full-length YAC128 HD mouse model, and associated transcriptional changes in hypothalamus and striatum. DR corrected many effects of the transgene including increased body weight, decreased blood glucose, and impaired motor function. These changes were associated with reduced striatal human (but not mouse) HTT expression, as well as alteration in gene expression regulating histone acetylation modifications, particularly Hdac2. Other mRNAs related to Huntington's pathology in striatal tissue showed significant modulation by the transgene, dietary restriction or both. These results establish a protective role of DR in a transgenic model that contains the complete human HTT gene and for the first time suggest a role for DR in lowering HTT level, which correlates with severity of symptoms.

Age-dependent alterations in the cortical entrainment of subthalamic nucleus neurons in the YAC128 mouse model of Huntington's disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that results in motor, cognitive and psychiatric abnormalities. Dysfunction in neuronal processing between the cortex and the basal ganglia is fundamental to the onset and progression of the HD phenotype. The corticosubthalamic hyperdirect pathway plays a crucial role in motor selection and blockade of neuronal activity in the subthalamic nucleus (STN) results in hyperkinetic movement abnormalities, similar to the motor symptoms associated with HD. The aim of the present study was to examine whether changes in the fidelity of information transmission between the cortex and the STN emerge as a function of phenotypic severity in the YAC128 mouse model of HD. We obtained in vivo extracellular recordings in the STN and concomitant electrocorticogram (ECoG) recordings during discrete brain states that reflected global cortical network synchronization or desynchronization. At early ages in YAC128 mice, both the cortex and the STN exhibited patterns of hyperexcitability. As symptom severity progressed, cortical entrainment of STN activity was disrupted and there was an increase in the proportion of non-oscillating, tonically firing STN neurons that were less phase-locked to cortical activity. Concomitant to the dissipation of STN entrainment, there was a reduction in the evoked response of STN neurons to focal cortical stimulation. The spontaneous discharge of STN neurons in YAC128 mice also decreased with age and symptom severity. These results indicate dysfunction in the flow of information within the corticosubthalamic circuit and demonstrate progressive age-related disconnection of the hyperdirect pathway in a transgenic mouse model of HD.

Partial rescue of some features of Huntington Disease in the genetic absence of caspase-6 in YAC128 mice

Huntington Disease (HD) is a progressive neurodegenerative disease caused by an elongated CAG repeat in the huntingtin (HTT) gene that encodes a polyglutamine tract in the HTT protein. Proteolysis of the mutant HTT protein (mHTT) has been detected in human and murine HD brains and is implicated in the pathogenesis of HD. Of particular importance is the site at amino acid (aa) 586 that contains a caspase-6 (Casp6) recognition motif.Activation of Casp6 occurs presymptomatically in human HD patients and the inhibition of mHTT proteolysis at aa586 in the YAC128 mouse model results in the full rescue of HD-like phenotypes. Surprisingly, Casp6 ablation in two different HD mouse models did not completely prevent the generation of this fragment, and therapeutic benefits were limited, questioning the role of Casp6 in the disease.We have evaluated the impact of the loss of Casp6 in the YAC128 mouse model of HD. Levels of the mHTT-586 fragment are reduced but not absent in the absence of Casp6 and we identify caspase 8 as an alternate enzyme that can generate this fragment. In vivo, the ablation of Casp6 results in a partial rescue of body weight gain, normalized IGF-1 levels, a reversal of the depression-like phenotype and decreased HTT levels. In the YAC128/Casp6−/− striatum there is a concomitant reduction in p62 levels, a marker of autophagic activity, suggesting increased autophagic clearance. These results implicate the HTT-586 fragment as a key contributor to certain features of HD, irrespective of the enzyme involved in its generation.

M07 Examining Conditional Caspase-6 Deficiency As A Therapeutic In Huntington Disease

<h3>Background</h3> Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterised by motor, cognitive, and psychiatric symptoms. HD is caused by a CAG repeat expansion in the huntingtin (HTT) gene resulting in the production of mutant huntingtin (mHTT). Caspase-6 (C6) is a protease that plays a central role in programmed cell death and has recently been implicated in several neurodegenerative diseases. Increased C6 activation is observed in human HD brains and in mouse models of HD, and genetic or peptide inhibition of C6 activity protects neurons from degeneration. C6 is one of several proteases that cleaves mHTT, and our lab has previously demonstrated that preventing C6-mediated cleavage of mHTT at the 586 amino acid site preserves striatal volume and rescues cognitive and motor deficits in the YAC128 mouse model of HD. These data point to an essential role for C6 in the pathogenesis of HD and provide a rationale for the inhibition of C6 as a therapeutic approach. <h3>Aim</h3> The goal of this study is to investigate the effects of genetically knocking out C6 in adulthood on the phenotype of the YAC128 mouse model of HD. <h3>Method</h3> Excision of the C6 gene in YAC128 mice will be carried out using the Cre/loxP system and by administering tamoxifen at 6 weeks of age. Treated mice will be examined for behavioural, neuropathological and biochemical endpoints. <h3>Results</h3> After extensive optimisation of tamoxifen administration, a treatment protocol was established to enable adequate excision of C6 in the brain. Mice have received 19 consecutive days of IP injections at 100mg/kg to induce excision and treated mice will be examined for behavioural, neuropathological and biochemical endpoints. <h3>Conclusions</h3> Results from this study will provide insight into the effect of adult C6 inhibition on HD pathogenesis and will further validate C6 as a therapeutic target in HD.

Silencing Mutant Huntingtin by Adeno-Associated Virus-Mediated RNA Interference Ameliorates Disease Manifestations in the YAC128 Mouse Model of Huntington's Disease

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease caused by an increase in the number of polyglutamine residues in the huntingtin (Htt) protein. With the identification of the underlying basis of HD, therapies are being developed that reduce expression of the causative mutant Htt. RNA interference (RNAi) that seeks to selectively reduce the expression of such disease-causing agents is emerging as a potential therapeutic strategy for this and similar disorders. This study examines the merits of administering a recombinant adeno-associated viral (AAV) vector designed to deliver small interfering RNA (siRNA) that targets the degradation of the Htt transcript. The aim was to lower Htt levels and to correct the behavioral, biochemical, and neuropathological deficits shown to be associated with the YAC128 mouse model of HD. Our data demonstrate that AAV-mediated RNAi is effective at transducing greater than 80% of the cells in the striatum and partially reducing the levels (~40%) of both wild-type and mutant Htt in this region. Concomitant with these reductions are significant improvements in behavioral deficits, reduction of striatal Htt aggregates, and partial correction of the aberrant striatal transcriptional profile observed in YAC128 mice. Importantly, a partial reduction of both the mutant and wild-type Htt levels is not associated with any notable overt neurotoxicity. Collectively, these results support the continued development of AAV-mediated RNAi as a therapeutic strategy for HD.

Antisense oligonucleotide-mediated correction of transcriptional dysregulation is correlated with behavioral benefits in the YAC128 mouse model of Huntington's disease.

Huntington's disease (HD) is a neurological disorder caused by mutations in the huntingtin (HTT) gene, the product of which leads to selective and progressive neuronal cell death in the striatum and cortex. Transcriptional dysregulation has emerged as a core pathologic feature in the CNS of human and animal models of HD. It is still unclear whether perturbations in gene expression are a consequence of the disease or importantly, contribute to the pathogenesis of HD. To examine if transcriptional dysregulation can be ameliorated with antisense oligonucleotides that reduce levels of mutant Htt and provide therapeutic benefit in the YAC128 mouse model of HD. Quantitative real-time PCR analysis was used to evaluate dysregulation of a subset of striatal genes in the YAC128 mouse model. Transcripts were then evaluated following ICV delivery of antisense oligonucleotides (ASO). Rota rod and Porsolt swim tests were used to evaluate phenotypic deficits in these mice following ASO treatment. Transcriptional dysregulation was detected in the YAC128 mouse model and appears to progress with age. ICV delivery of ASOs directed against mutant Htt resulted in reduction in mutant Htt levels and amelioration in behavioral deficits in the YAC128 mouse model. These improvements were correlated with improvements in the levels of several dysregulated striatal transcripts. The role of transcriptional dysregulation in the pathogenesis of Huntington's disease is not well understood, however, a wealth of evidence now strongly suggests that changes in transcriptional signatures are a prominent feature in the brains of both HD patients and animal models of the disease. Our study is the first to show that a therapeutic agent capable of improving an HD disease phenotype is concomitantly correlated with normalization of a subset of dysregulated striatal transcripts. Our data suggests that correction of these disease-altered transcripts may underlie, at least in part, the therapeutic efficacy shown associated with ASO-mediated correction of HD phenotypes and may provide a novel set of early biomarkers for evaluating future therapeutic concepts for HD.

NP03, a novel low-dose lithium formulation, is neuroprotective in the YAC128 mouse model of Huntington disease

Huntington disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene, remains without a treatment to modify the course of the illness. Lithium, a drug widely used for the treatment of bipolar disorder, has been shown to exert neuroprotective effects in a number of models of neurological disease but may have various toxic effects at conventional therapeutic doses. We examined whether NP03, a novel low-dose lithium microemulsion, would improve the disease phenotypes in the YAC128 mouse model of HD. We demonstrate that NP03 improves motor function, ameliorates the neuropathological deficits in striatal volume, neuronal counts, and DARPP-32 expression, and partially rescues testicular atrophy in YAC128 mice. These positive effects were accompanied by improvements in multiple biochemical endpoints associated with the pathogenesis of HD, including normalization of caspase-6 activation and amelioration of deficits in BDNF levels, and with no lithium-related toxicity. Our findings demonstrate that NP03 ameliorates the motor and neuropathological phenotypes in the YAC128 mouse model of HD, and represents a potential therapeutic approach for HD.

Decreasing Levels of the cdk5 Activators, p25 and p35, Reduces Excitotoxicity in Striatal Neurons

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expanded CAG trinucleotide repeat sequence in the huntingtin gene. The resulting poly-glutamine expansion in the huntingtin protein imparts a novel toxic gain of function causing selective loss of medium spiny neurons (MSNs) in the striatum. Although the exact mechanism of cell death is unclear, recent evidence suggests involvement of NMDA-receptor mediated excitotoxicity and aberrant cyclin dependent kinase 5 (cdk5) activity in striatal cells undergoing neurodegeneration. In this study we directly tested the effect of reduced levels of p25 and p35, two proteins required for cdk5 activation, on striatal neurodegeneration using mice with targeted deletion of p35. Quinolinic acid (QA) injected into the striatum of mice causes NMDA-receptor mediated cell death, and these QA-induced striatal lesions were examined in p35 hemizygous null (p35+/-) and wildtype (WT) mice. Striatal QA lesion volumes were 30% smaller in p35+/- mice than in WT mice. Furthermore, primary neuronal cultures of MSNs from P0 p35+/- pups displayed 33% less apoptotic neurons following NMDA treatment than those from WT pups. Examination of YAC128 mouse model of HD showed elevated p25 levels in striatum following intrastriatal QA injection. Our findings provide direct evidence for p25 and p35 involvement in excitotoxic neurodegeneration of MSNs and suggest a role for the cdk5 pathway in HD striatal neurodegeneration.

Caspase-6-Resistant Mutant Huntingtin Does not Rescue the Toxic Effects of Caspase-Cleavable Mutant Huntingtin in vivo.

The amelioration of behavioral and neuropathological deficits in mice expressing caspase-6-resistant (C6R) mutant huntingtin (mhtt), despite the presence of an expanded polyglutamine tract, highlights proteolysis of htt at the 586aa caspase-6 (casp6) site may be an important mechanism in the pathogenesis of Huntington disease (HD). One possible explanation of these effects is that C6R mhtt could act as a dominant negative on mhtt. To determine if the neuroprotective effect observed in the C6R mice is due to dominant negative effects, we crossed the C6R mice to the YAC128 HD mouse model to generate mice expressing both caspase-cleavable and C6R mhtt (YAC/C6R) concurrently and assessed previously defined behavioral and neuropathological endpoints. Our results demonstrate that YAC/C6R animals exhibit similar motor abnormalities and learning deficits as the YAC128 mice. Neuropathological analysis reveals a significant decrease in brain weight and striatal volume in the YAC/C6R mice comparable to the YAC128 mice. In contrast, and similar to previous findings, C6R mice demonstrate preserved brain weight and striatal volume. As expected, body weight is significantly increased in the YAC/C6R mice due to the increased levels of htt. The results of this study suggest that the lack of an HD phenotype in the C6R mice is most likely due to the absence of cleavage of htt and not due to suppression of expression of mhtt.

Age-dependent neurovascular abnormalities and altered microglial morphology in the YAC128 mouse model of Huntington disease

Central nervous system (CNS) inflammatory processes including microglial activation have been implicated in the pathogenesis of neurodegenerative diseases such as Huntington Disease (HD). We report age-dependent changes in striatal microglial morphology and vasculature in the YAC128 mouse model of HD. Decreases in microglial ramification along with a decrease in vessel diameter and increased vessel density and length suggest the presence of microgliosis and proangiogenic activity in YAC128 mice. Our hypothesis for this study was that the changes in microglial morphology and perturbations in vasculature may be involved in the pathogenesis of HD and that peripheral challenge with the bacterial endotoxin, lipopolysaccharide (LPS), will exacerbate these microglial and vascular changes as well as the HD phenotype in YAC128 mice at 12months. Chronic peripheral LPS (1mg/kg) potentiated microglial activation indicated by an increase in microglial cell body size and retraction of processes. This potentiation in microglial activation with chronic peripheral LPS challenge was paralleled with vascular remodeling including dilatation, increased vessel wall thickness, increased BBB permeability and fibrinogen deposition in YAC128 striatum. Although peripheral LPS caused an increase in microglial activation and degenerative changes in cerebrovasculature, the phenotypic hallmarks of HD in YAC128 mice such as motor coordination deficits and decreased striatal volume were not exacerbated by chronic peripheral LPS exposure. This study identifies age-dependent increases in microglial activation and angiogenesis in YAC128 at 12months. Peripheral inflammation induced by chronic LPS causes similar changes but does not influence the HD phenotype in YAC128 mice.

Altered palmitoylation and neuropathological deficits in mice lacking HIP14

Huntingtin interacting protein 14 (HIP14, ZDHHC17) is a huntingtin (HTT) interacting protein with palmitoyl transferase activity. In order to interrogate the function of Hip14, we generated mice with disruption in their Hip14 gene. Hip14-/- mice displayed behavioral, biochemical and neuropathological defects that are reminiscent of Huntington disease (HD). Palmitoylation of other HIP14 substrates, but not Htt, was reduced in the Hip14-/- mice. Hip14 is dysfunctional in the presence of mutant htt in the YAC128 mouse model of HD, suggesting that altered palmitoylation mediated by HIP14 may contribute to HD.

Expression analysis of novel striatal-enriched genes in Huntington disease

Selective degeneration of striatal neurons is a pathologic hallmark of Huntington disease (HD). The exact mechanism(s) behind this specific neurodegeneration is still unknown. Expression studies of diseased human post-mortem brain, as well as different mouse models exhibiting striatal degeneration, have demonstrated changes in the expression of many important genes with a large proportion of changes being observed in the striatal-enriched genes. These investigations have raised questions about how enrichment of particular transcripts in the striatum can lead to its selective vulnerability to neurodegeneration. Monitoring the expression changes of striatal-enriched genes during the course of the disease may be informative about their potential involvement in selective degeneration. In this study, we analyzed a Serial Analysis of Gene Expression (SAGE) database (www.mouseatlas.org) and compared the mouse striatum to 18 other brain regions to generate a novel list of striatal-enriched transcripts. These novel striatal-enriched transcripts were subsequently evaluated for expression changes in the YAC128 mouse model of HD, and differentially expressed transcripts were further examined in human post-mortem caudate samples. We identified transcripts with altered expression in YAC128 mice, which also showed consistent expression changes in human post-mortem tissue. The identification of novel striatal-enriched genes with altered expression in HD offers new avenues of study, leading towards a better understanding of specific pathways involved in the selective degeneration of striatal neurons in HD.

CREB is a key regulator of striatal vulnerability in chemical and genetic models of Huntington's disease

Evidence of dysregulation of the CREB/CRE transcriptional pathway in animal models of Huntington's disease (HD) suggests that strategies designed to augment CRE-mediated transcription may be of therapeutic value. Here, we investigated the consequences of CREB activation and repression in chemical and transgenic mouse models of HD. In the 3-nitropropionic acid (3-NP) model, CREB phospho-activation in the striatum was potently repressed within the neurotoxic “core” region prior to cell death. Conversely, marked expression of phospho-CREB, as well the CREB-regulated cytoprotective gene Bcl-2, was detected in the “penumbral” region. To examine potential contributory roles for the CREB/CRE transcriptional pathway in striatal degeneration, we used both CREB loss- (A-CREB) and gain- (VP16-CREB) of-function transgenic mouse strains. 3-NP-induced striatal lesion size and motor dysfunction were significantly increased in A-CREB mice compared to controls. Conversely, striatal damage and motor deficits were diminished in VP16-CREB mice. Furthermore, transgenic A-CREB significantly accelerated motor impairment in the YAC128 mouse model of HD. Together, these results indicate that CREB functionality is lost during the early stages of striatal cell stress and that the repression of CREB-mediated transcription contributes to the pathogenic process.

Mutant Huntingtin N-terminal Fragments of Specific Size Mediate Aggregation and Toxicity in Neuronal Cells

Huntingtin proteolysis is implicated in Huntington disease pathogenesis, yet, the nature of huntingtin toxic fragments remains unclear. Huntingtin undergoes proteolysis by calpains and caspases within an N-terminal region between amino acids 460 and 600. We have focused on proteolytic steps producing shorter N-terminal fragments, which we term cp-1 and cp-2 (distinct from previously described cp-A/cp-B). We used HEK293 cells to express the first 511 residues of huntingtin and further define the cp-1 and cp-2 cleavage sites. Based on epitope mapping with huntingtin-specific antibodies, we found that cp-1 cleavage occurs between residues 81 and 129 of huntingtin. Affinity and size exclusion chromatography were used to further purify huntingtin cleavage products and enrich for the cp-1/cp-2 fragments. Using mass spectrometry, we found that the cp-2 fragment is generated by cleavage of huntingtin at position Arg(167). This site was confirmed by deletion analysis and specific detection with a custom-generated cp-2 site neo-epitope antibody. Furthermore, alterations of this cleavage site resulted in a decrease in toxicity and an increase in aggregation of huntingtin in neuronal cells. These data suggest that cleavage of huntingtin at residue Arg(167) may mediate mutant huntingtin toxicity in Huntington disease.

Differential Susceptibility to Excitotoxic Stress in YAC128 Mouse Models of Huntington Disease between Initiation and Progression of Disease

Huntington disease (HD) is a neurodegenerative disorder caused by an expanded CAG tract in the HD gene. Polyglutamine expansion of huntingtin (htt) results in early, progressive loss of medium spiny striatal neurons, as well as cortical neurons that project to the striatum. Excitotoxicity has been postulated to play a key role in the selective vulnerability of striatal neurons in HD. Early excitotoxic neuropathological changes observed in human HD brain include increased quinolinate (QUIN) concurrent with proliferative changes such as increased spine density and dendritic length. In later stages of the disease, degenerative-type changes are apparent, such as loss of dendritic arborization, a reduction in spine density and reduced levels of 3-hydroxykynurenine and QUIN. It is currently unknown whether sensitivity to excitotoxic stress varies between initiation and progression of disease. Here, we have assessed the excitotoxic phenotype in the YAC128 mouse model of HD by examining the response to excitotoxic stress at different stages of disease. Our results demonstrate that YAC128 mice display enhanced sensitivity to NMDA ex vivo and QUIN in vivo before obvious phenotypic changes. In contrast, 10-month-old symptomatic YAC128 mice are resistant to QUIN-induced neurotoxicity. These findings are paralleled by a significant increase in NMDAR-mediated membrane currents in presymptomatic YAC128 dissociated medium spiny neurons progressing to reduced NMDAR-mediated membrane currents with disease progression. These data highlight the dynamic nature of the mutant htt-mediated excitotoxic phenotype and suggests that therapeutic approaches to HD may need to be altered, depending on the stage and development of the disease.

Ginsenosides protect striatal neurons in a cellular model of Huntington's disease

Ginseng, the root of Panax ginseng C.A. Meyer (Araliaceae), is a widely used herbal medicine. Ginsenosides, the active ingredients of ginseng, are the main components responsible for many beneficial actions of ginseng. In the present study, we tested 10 different ginsenosides in the previously developed in vitro Huntington's disease (HD) assay with primary medium spiny striatal neuronal cultures (MSN) from the YAC128 HD mouse model. We found that nanomolar concentrations of ginsenoside Rb1 and Rc effectively protected YAC128 medium spiny neurons from glutamate-induced apoptosis and that Rg5 was protective at micromolar concentration. The other seven ginsenosides tested were not effective or exerted toxic effects in MSN cultures. From further experiments, we suggested that neuroprotective effects of ginsenosides Rb1, Rc, and Rg5 could correlate with their ability to inhibit glutamate-induced Ca(2+) responses in cultured MSN. From these results we concluded that ginsenosides Rb1, Rc, and Rg5 offer a potential therapeutic choice for the treatment of HD and possibly other neurodegenerative disorders.

Automated deformation analysis in the YAC128 Huntington disease mouse model

The YAC128 mouse recapitulates many of the clinical features of Huntington disease (HD), including selective neuropathology with neuronal loss. Here we investigate whether differences in neuroanatomy could be detected using high-resolution magnetic resonance (MR) imaging earlier than the previously defined 9-month age of onset of striatal neuropathology. The striatum is significantly decreased in volume (3.4%, p << 0.02) at 8 months of age. A subset of the brains was also analyzed using stereology, and the MR measures were found to be more robust at separating the two groups of mice. Striatal degeneration was found to be asymmetric, with the dorsal and lateral aspects of the striatum being most affected. Non-striatal changes in neuroanatomy were also investigated, revealing regions of expansion as well as atrophy. Our findings suggest that MR imaging can be used to detect and monitor subtle anatomical differences throughout the whole brain and at early time points in the YAC128 mouse-model of HD.

Selective degeneration and nuclear localization of mutant huntingtin in the YAC128 mouse model of Huntington disease

Huntington disease (HD) is an adult onset neurodegenerative disorder that predominantly affects the striatum and cortex despite ubiquitous expression of mutant huntingtin (htt). Here we demonstrate that this pattern of selective degeneration is present in the YAC128 mouse model of HD. At 12 months, YAC128 mice show significant atrophy in the striatum, globus pallidus and cortex with relative sparing of the hippocampus and cerebellum (striatum: -10.4%, P<0.001; globus pallidus: -10.8%, P=0.04; cortex: -8.6%, P=0.001; hippocampus: +0.3%, P=0.9; cerebellum: +2.9%, P=0.6). Similarly, neuronal loss at this age is present in the striatum (-9.1%, P<0.001) and cortex of YAC128 mice (-8.3%, P=0.02) but is not detected in the hippocampus (+1.5%, P=0.72). Mutant htt expression levels are similar throughout the brain and fail to explain the selective neuronal degeneration. In contrast, nuclear detection of mutant htt occurs earliest and to the greatest extent in the striatum-the region most affected in HD. The appearance of EM48-reactive mutant htt in the nucleus in the striatum at 2 months coincides with the onset of behavioral abnormalities in YAC128 mice. In contrast to YAC128 mice, the R6/1 mouse model of HD, which expresses exon 1 of mutant htt, exhibits non-selective, widespread atrophy along with non-selective nuclear detection of mutant htt at 10 months of age. Our findings suggest that selective nuclear localization of mutant htt may contribute to the selective degeneration in HD and that appropriately regulated expression of full-length mutant htt in YAC128 mice results in a pattern of degeneration remarkably similar to human HD.

Ethyl-EPA treatment improves motor dysfunction, but not neurodegeneration in the YAC128 mouse model of Huntington disease

Huntington disease (HD) is an adult-onset neurodegenerative disorder that is characterized by selective degeneration in the striatum. There are currently no treatments that can prevent the progressive decline of motor and cognitive function in HD. In parallel with a human clinical trial, we examined the efficacy of ethyl-EPA treatment in the YAC128 mouse model of HD. Oral delivery of ethyl-EPA to symptomatic YAC128 mice beginning at 7 months of age increased membrane EPA levels 3-fold ( P < 0.001) and resulted in a modest but significant improvement in motor dysfunction by 12 months of age as measured by open-field activity ( P = 0.01) and performance on the rotarod ( P = 0.05). At this age, ethyl-EPA-treated YAC128 mice showed no improvement in striatal volume, striatal neuron counts, striatal neuronal cross-sectional area, or striatal DARPP-32 expression compared to untreated YAC128 mice, thereby indicating no reduction of striatal neuropathology. This result is congruent with modest motor benefits observed in HD patients treated with ethyl-EPA. Overall, this work demonstrates the feasibility of experimental therapeutics in the YAC128 mouse model and suggests that experiments in these mice may be predictive for future human clinical trials.