Transgenic Mouse Model Of Huntington's Disease Research Articles

Impaired α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor Trafficking and Function by Mutant Huntingtin

Emerging evidence from studies of Huntington disease (HD) pathophysiology suggests that huntingtin (htt) and its associated protein HAP1 participate in intracellular trafficking and synaptic function. However, it is largely unknown whether AMPA receptor trafficking, which is crucial for controlling the efficacy of synaptic excitation, is affected by the mutant huntingtin with polyglutamine expansion (polyQ-htt). In this study, we found that expressing polyQ-htt in neuronal cultures significantly decreased the amplitude and frequency of AMPAR-mediated miniature excitatory postsynaptic current (mEPSC), while expressing wild-type huntingtin (WT-htt) increased mEPSC. AMPAR-mediated synaptic transmission was also impaired in a transgenic mouse model of HD expressing polyQ-htt. The effect of polyQ-htt on mEPSC was mimicked by knockdown of HAP1 and occluded by the dominant negative HAP1. Moreover, we found that huntingtin affected mESPC via a mechanism depending on the kinesin motor protein, KIF5, which controls the transport of GluR2-containing AMPARs along microtubules in dendrites. The GluR2/KIF5/HAP1 complex was disrupted and dissociated from microtubules in the HD mouse model. Together, these data suggest that AMPAR trafficking and function is impaired by mutant huntingtin, presumably due to the interference of KIF5-mediated microtubule-based transport of AMPA receptors. The diminished strength of glutamatergic transmission could contribute to the deficits in movement control and cognitive processes in HD conditions.

PPARgamma rescue of the mitochondrial dysfunction in Huntington's disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The resultant mutant Htt protein (mHtt) forms aggregates in the brain (e.g., cortex and striatum), and causes devastating neuronal degeneration. Transcriptional dysfunction caused by mHtt is critical for HD. We recently demonstrated that a crucial transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) played a major function in the energy homeostasis observed in HD and that PPARγ is a potentially neuroprotective target for this disease. We report here that the transcript level of PPARγ was markedly downregulated in the cortex of a transgenic mouse model of HD (R6/2). Treatment of R6/2 mice with an agonist of PPARγ (thiazolidinedione, TZD) resulted in a beneficial effect on PPARγ. By reducing Htt aggregates and thereby ameliorating the recruitment of PPARγ into Htt aggregates, TZD treatment also elevated the availability of PPARγ level and subsequently normalized the expression of downstream genes (including PGC-1α and several mitochondrial genes) in the cortex. The above protective effects appeared to be exerted by a direct activation of the PPARγ agonist (rosiglitazone) because rosiglitazone protected a neuroblastoma cell line (N2A) from mHtt-evoked mitochondrial deficiency. Our results reveal that TZD and rosiglitazone may play a protective role in HD, and support the view that PPARγ is a potential therapeutic target in HD.

Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease.

Huntington disease (HD) is a devastating neurodegenerative disorder for which there are no disease-modifying treatments. Previous studies have proposed that activation of the heat shock response (HSR) via the transcription factor heat shock factor 1 (HSF1) may be of therapeutic benefit. However, the effect of disease progression on the HSR and the therapeutic potential of this pathway are currently unknown. Here, we used a brain-penetrating HSP90 inhibitor and physiological, molecular, and behavioral readouts to demonstrate that pharmacological activation of HSF1 improves huntingtin aggregate load, motor performance, and other HD-related phenotypes in the R6/2 mouse model of HD. However, the beneficial effects of this treatment were transient and diminished with disease progression. Molecular analyses to understand the transient nature of these effects revealed altered chromatin architecture, reduced HSF1 binding, and impaired HSR accompanied disease progression in both the R6/2 transgenic and HdhQ150 knockin mouse models of HD. Taken together, our findings reveal that the HSR, a major inducible regulator of protein homeostasis and longevity, is disrupted in HD. Consequently, pharmacological induction of HSF1 as a therapeutic approach to HD is more complex than was previously anticipated.

A New Drug Design Targeting the Adenosinergic System for Huntington's Disease

BackgroundHuntington's disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The expanded CAG repeats are translated into polyglutamine (polyQ), causing aberrant functions as well as aggregate formation of mutant Htt. Effective treatments for HD are yet to be developed.Methodology/Principal FindingsHere, we report a novel dual-function compound, N 6-(4-hydroxybenzyl)adenine riboside (designated T1-11) which activates the A2AR and a major adenosine transporter (ENT1). T1-11 was originally isolated from a Chinese medicinal herb. Molecular modeling analyses showed that T1-11 binds to the adenosine pockets of the A2AR and ENT1. Introduction of T1-11 into the striatum significantly enhanced the level of striatal adenosine as determined by a microdialysis technique, demonstrating that T1-11 inhibited adenosine uptake in vivo. A single intraperitoneal injection of T1-11 in wildtype mice, but not in A2AR knockout mice, increased cAMP level in the brain. Thus, T1-11 enters the brain and elevates cAMP via activation of the A2AR in vivo. Most importantly, addition of T1-11 (0.05 mg/ml) to the drinking water of a transgenic mouse model of HD (R6/2) ameliorated the progressive deterioration in motor coordination, reduced the formation of striatal Htt aggregates, elevated proteasome activity, and increased the level of an important neurotrophic factor (brain derived neurotrophic factor) in the brain. These results demonstrate the therapeutic potential of T1-11 for treating HD.Conclusions/SignificanceThe dual functions of T1-11 enable T1-11 to effectively activate the adenosinergic system and subsequently delay the progression of HD. This is a novel therapeutic strategy for HD. Similar dual-function drugs aimed at a particular neurotransmitter system as proposed herein may be applicable to other neurotransmitter systems (e.g., the dopamine receptor/dopamine transporter and the serotonin receptor/serotonin transporter) and may facilitate the development of new drugs for other neurodegenerative diseases.

The dysfunction of hepatic transcriptional factors in mice with Huntington's Disease

Huntington's Disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The resultant mutant Htt protein (mHtt) forms aggregates in the brain and several peripheral tissues (e.g., the liver), and causes devastating widespread pathology. Since aggregates of mHtt have been found in the liver, defects in liver function might contribute to peripheral abnormalities in HD mice. We previously reported that two crucial transcription factors PPARγ (peroxisome proliferator-activated receptor-γ) and C/EBPα (CCAAT/enhancer-binding protein α) are potential therapeutic targets of HD. We herein demonstrate that the transcript level of PPARγ was markedly downregulated in the livers of a transgenic mouse model of HD (R6/2). Treatment of R6/2 mice with an agonist of PPARγ (thiazolidinedione, TZD) normalized the reduced PPARγ transcript. By reducing Htt aggregates and thereby ameliorating the recruitment of PPARγ into Htt aggregates, TZD treatment also elevated the availability of the PPARγ level and subsequently normalized the expression of its downstream genes [including PGC-1α (PPAR coactivator-1α) and several mitochondrial genes] and C/EBPα in the liver. The aforementioned protective effects appeared to be exerted by a direct activation of the PPARγ agonist (rosiglitazone) because rosiglitazone reduced mHtt aggregates and rescued energy deficiency in a hepatoma cell line (HepG2). These findings show that the impairment of PPARγ contributes to the liver dysfunction observed in HD. Treatment with PPARγ agents (TZD and rosiglitazone) enhanced the function of PPARγ, and might lead to therapeutic benefits.

Neuroprotective effects of creatine

There is a substantial body of literature, which has demonstrated that creatine has neuroprotective effects both in vitro and in vivo. Creatine can protect against excitotoxicity as well as against β-amyloid toxicity in vitro. We carried out studies examining the efficacy of creatine as a neuroprotective agent in vivo. We demonstrated that creatine can protect against excitotoxic lesions produced by N-methyl-D: -aspartate. We also showed that creatine is neuroprotective against lesions produced by the toxins malonate and 3-nitropropionic acid (3-NP) which are reversible and irreversible inhibitors of succinate dehydrogenase, respectively. Creatine produced dose-dependent neuroprotective effects against MPTP toxicity reducing the loss of dopamine within the striatum and the loss of dopaminergic neurons in the substantia nigra. We carried out a number of studies of the neuroprotective effects of creatine in transgenic mouse models of neurodegenerative diseases. We demonstrated that creatine produced an extension of survival, improved motor performance, and a reduction in loss of motor neurons in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). Creatine produced an extension of survival, as well as improved motor function, and a reduction in striatal atrophy in the R6/2 and the N-171-82Q transgenic mouse models of Huntington's disease (HD), even when its administration was delayed until the onset of disease symptoms. We recently examined the neuroprotective effects of a combination of coenzyme Q10 (CoQ10) with creatine against both MPTP and 3-NP toxicity. We found that the combination of CoQ and creatine together produced additive neuroprotective effects in a chronic MPTP model, and it blocked the development of alpha-synuclein aggregates. In the 3-NP model of HD, CoQ and creatine produced additive neuroprotective effects against the size of the striatal lesions. In the R6/2 transgenic mouse model of HD, the combination of CoQ and creatine produced additive effects on improving survival. Creatine may stabilize mitochondrial creatine kinase, and prevent activation of the mitochondrial permeability transition. Creatine, however, was still neuroprotective in mice, which were deficient in mitochondrial creatine kinase. Administration of creatine increases the brain levels of creatine and phosphocreatine. Due to its neuroprotective effects, creatine is now in clinical trials for the treatment of Parkinson's disease (PD) and HD. A phase 2 futility trial in PD showed approximately a 50% improvement in Unified Parkinson's Disease Rating Scale at one year, and the compound was judged to be non futile. Creatine is now in a phase III clinical trial being carried out by the NET PD consortium. Creatine reduced plasma levels of 8-hydroxy-2-deoxyguanosine in HD patients phase II trial and was well-tolerated. Creatine is now being studied in a phase III clinical trial in HD, the CREST trial. Creatine, therefore, shows great promise in the treatment of a variety of neurodegenerative diseases.

Necrostatin-1 ameliorates symptoms in R6/2 transgenic mouse model of Huntington's disease

Necrostatin-1 ameliorates symptoms in R6/2 transgenic mouse model of Huntington's disease

Neuroprotective effects of a novel kynurenic acid analogue in a transgenic mouse model of Huntington’s disease

Huntington's disease (HD) is a progressive neurodegenerative disorder, the pathomechanism of which is not yet fully understood. Excitotoxicity is known to be involved in the development of HD and antiglutamatergic agents may, therefore, have beneficial neuroprotective effects. One of these agents is the tryptophan metabolite kynurenic acid (KYNA), which is an endogenous NMDA receptor antagonist. However, its pharmacological properties rule out its systemic administration in CNS disorders. We have tested a novel KYNA analogue, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride, in the N171-82Q transgenic mouse model of HD. The analogue exhibited several significant effects: it prolonged the survival of the transgenic mice, ameliorated their hypolocomotion, prevented the loss of weight and completely prevented the atrophy of the striatal neurons. The beneficial effects of this KYNA analogue are probably explained by its complex anti-excitotoxic activity. As it did not induce any appreciable side-effect at the protective dose applied in a chronic dosing regime in this mouse model, it appears worthy of further thorough investigations with a view to eventual clinical trials.

Neuropeptide Y modifies the disease course in the R6/2 transgenic model of Huntington's disease

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by progressive neuronal dysfunction and cell loss, especially striatal GABAergic neurons, generating motor, cognitive and affective problems. Although the disease-causing gene is known, the exact mechanism by which it induces its pathological effect remains unknown, and no cure is currently available for this disease. Interestingly, striatal neurons that express neuropeptide Y (NPY) are preferentially spared in HD and the number of such cells is increased in the striatum of HD patients. Furthermore, neurogenesis in the subventricular zone (SVZ) also appears to be up-regulated in HD patients, and previously we also demonstrated in wild-type mice that intracerebroventricular (ICV) NPY promotes SVZ neurogenesis with migration of the newborn cells towards the striatum where they differentiate into GABAergic neurons. Therefore, we sought to determine whether NPY could be of therapeutic benefit in a transgenic mouse model of HD (R6/2) through an action on SVZ neurogenesis. We found that a single ICV injection of NPY in R6/2 mice increased survival time through reduced weight loss as well as having a beneficial effect on motor function as evidenced by improving rotarod performance and reducing paw-clasping. We also demonstrated that the degree of cerebral and striatal atrophy was reduced following such a single NPY injection and that whilst the peptide also increased the number of BrdU-positive cells in the SVZ (but not in the dentate gyrus) of R6/2 mice, this was not sufficient to account for the changes in anatomy and function that we found.. These results suggest that NPY may be of some therapeutic interest in patients with HD, although further work is needed to ascertain exactly how it mediates its beneficial effects.

Resveratrol protects against peripheral deficits in a mouse model of Huntington's disease

Sirtuins are NAD-dependent deacetylases that regulate important biologic processes including transcription, cell survival and metabolism. Activation of SIRT1, a mammalian sirtuin, extends longevity and increases neuronal survival. An important substrate of SIRT1 is peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α), a principal regulator of energy metabolism, whose function is significantly impaired in Huntington's disease (HD). We studied the effects of a pharmacological preparation of the SIRT1 activator resveratrol (SRT501-M), in the N171-82Q transgenic mouse model of HD. We analyzed motor performance, survival, central and peripheral pathology and levels of PGC-1α expression. Administration of SRT501-M increased expression of PGC-1α, as well as its downstream targets, nuclear respiratory factor-1 (NRF-1) and uncoupling protein-1 (UCP-1) in brown adipose tissue (BAT), but there was no effect on PGC-1α, NRF-1 or the mitochondrial transcription factor (Tfam) in the striatum. SRT501-M administration also reduced BAT vacuolation and decreased elevated blood glucose levels. However, there was no significant improvement in weight loss, motor performance, survival and striatal atrophy. Activation of the PGC-1α signaling pathway via resveratrol-induced activation of SIRT1, therefore, is an effective therapy in BAT, but not in the central nervous system of HD transgenic mice.

Functional roles of the AMP‐activated protein kinase in Huntington's disease

Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of CAG trinucleotide repeats in Huntingtin (Htt) gene. Accumulated evidence from different laboratories suggests the involvement of energy metabolism, excitotoxicity, and oxidative stress in HD pathogenesis. The common pathways linking Htt mutation with energy deficiency in HD remain largely unknown. We reported herein that a metabolic sensor (AMP‐activated protein kinase, AMPK) was overactivated in striatal cell lines (ST14A; STHdhQ7, STHdhQ109), as well as brains of a transgenic mouse model of HD (R6/2) and human HD patients. AMPK is a downstream mediator of many different types of stress. It composes a catalytic (α) and two regulatory subunits (β and γ), and can be activated by CaMKK and LKB1 via phosphorylation at the threonine residue 172 of AMPKα. In addition to suppressing metabolic enzymes (e.g., acetyl‐CoA carboxylase) and reducing ATP consumption upon stress, AMPK also phosphorylates a wide variety of proteins with different functions. We demonstrated in the present study that an agonist (CGS21680) of the A2A adenosine receptor (A2A receptor) not only produced beneficial effects on several major symptoms of HD in R6/2 mice, it also normalized the overactivated AMPK via a cAMP/protein kinase A‐ dependent pathway. Our findings shed new light on the metabolic aspects as well as the protective effects of cAMP‐elevating reagents in HD.

Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington's disease

Oxidative stress is a prominent feature of Huntington's disease (HD) due to mitochondrial dysfunction and the ensuing overproduction of reactive oxygen species (ROS). This phenomenon ultimately contributes to cognitive and motor impairment, as well as brain pathology, especially in the striatum. Targeting the transcription of the endogenous antioxidant machinery could be a promising therapeutic approach. The NF-E2-related factor-2 (Nrf2)/antioxidant response element (ARE) signaling pathway is an important pathway involved in antioxidant and anti-inflammatory responses. Synthetic triterpenoids, which are derived from 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic acid (CDDO) activate the Nrf2/ARE pathway and reduce oxidative stress in animal models of neurodegenerative diseases. We investigated the effects of CDDO-ethyl amide (CDDO-EA) and CDDO-trifluoroethyl amide (CDDO-TFEA) in N171-82Q mice, a transgenic mouse model of HD. CDDO-EA or CDDO-TFEA were administered in the diet at various concentrations, starting at 30days of age. CDDO-EA and CDDO-TFEA upregulated Nrf2/ARE induced genes in the brain and peripheral tissues, reduced oxidative stress, improved motor impairment and increased longevity. They also rescued striatal atrophy in the brain and vacuolation in the brown adipose tissue. Therefore compounds targeting the Nrf2/ARE pathway show great promise for the treatment of HD.

Ex vivo delivery of GDNF maintains motor function and prevents neuronal loss in a transgenic mouse model of Huntington's disease

Huntington's disease (HD) is an autosomal dominant disorder caused by expansion of polyglutamine repeats in the huntingtin gene leading to loss of striatal and cortical neurons followed by deficits in cognition and choreic movements. Growth factor delivery to the brain has shown promise in various models of neurodegenerative diseases, including HD, by reducing neuronal death and thus limiting motor impairment. Here we used mouse neural progenitor cells (mNPCs) as growth factor delivery vehicles in the N171-82Q transgenic mouse model of HD. mNPCs derived from the developing mouse striatum were isolated and infected with lentivirus expressing either glial cell line-derived neurotrophic factor (GDNF) or green fluorescent protein (GFP). Next, mNPCs GDNF or mNPCs GFP were transplanted bilaterally into the striatum of pre-symptomatic N171-82Q mice. We found that mNPCs GDNF, but not mNPCs GFP, maintained rotarod function and increased striatal neuron survival out to 3 months post-transplantation. Importantly, histological analysis showed GDNF expression through the duration of the experiment. Our data show that mNPCs GDNF can survive transplantation, secrete GDNF for several weeks and are able to maintain motor function in this model of HD.

CalDAG-GEFI down-regulation in the striatum as a neuroprotective change in Huntington's disease

Huntingtin protein (Htt) is ubiquitously expressed, yet Huntington's disease (HD), a fatal neurologic disorder produced by expansion of an Htt polyglutamine tract, is characterized by neurodegeneration that occurs primarily in the striatum and cerebral cortex. Such discrepancies between sites of expression and pathology occur in multiple neurodegenerative disorders associated with expanded polyglutamine tracts. One possible reason is that disease-modifying factors are tissue-specific. Here, we show that the striatum-enriched protein, CalDAG-GEFI, is severely down-regulated in the striatum of mouse HD models and is down-regulated in HD individuals. In the R6/2 transgenic mouse model of HD, striatal neurons with the largest aggregates of mutant Htt have the lowest levels of CalDAG-GEFI. In a brain-slice explant model of HD, knock-down of CalDAG-GEFI expression rescues striatal neurons from pathology induced by transfection of polyglutamine-expanded Htt exon 1. These findings suggest that the striking down-regulation of CalDAG-GEFI in HD could be a protective mechanism that mitigates Htt-induced degeneration.

Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF

In this study we tested whether phosphodiesterase 5 (PDE5) inhibitors, sildenafil and vardenafil, would afford protection against 3-nitropropionic acid (3NP), which produces striatal lesions that closely mimic some of the neuropathological features of Huntington's Disease (HD). The neurotoxin was given over 5 days by constant systemic infusion using osmotic minipumps. Animals treated with PDE5 inhibitors (sildenafil or vardenafil) showed improved neurologic scores, reduced the loss of striatal DARPP-32 protein levels and lesion volumes, and decreased calpain activation produced by 3NP. This protective effect was independent of changes in 3NP-induced succinate dehydrogenase inhibition. Furthermore, striatal p-CREB levels along with the expression of BDNF were significantly increased in sildenafil-treated rats. In summary, PDE5 inhibitors protected against 3NP-induced striatal degeneration by reducing calpain activation and by promoting survival pathways. These data encourage further evaluation of PDE5 inhibitors in transgenic mouse models of HD.

Transcriptional changes in Huntington disease identified using genome-wide expression profiling and cross-platform analysis

Evaluation of transcriptional changes in the striatum may be an effective approach to understanding the natural history of changes in expression contributing to the pathogenesis of Huntington disease (HD). We have performed genome-wide expression profiling of the YAC128 transgenic mouse model of HD at 12 and 24 months of age using two platforms in parallel: Affymetrix and Illumina. The data from these two powerful platforms were integrated to create a combined rank list, thereby revealing the identity of additional genes that proved to be differentially expressed between YAC128 and control mice. Using this approach, we identified 13 genes to be differentially expressed between YAC128 and controls which were validated by quantitative real-time PCR in independent cohorts of animals. In addition, we analyzed additional time points relevant to disease pathology: 3, 6 and 9 months of age. Here we present data showing the evolution of changes in the expression of selected genes: Wt1, Pcdh20 and Actn2 RNA levels change as early as 3 months of age, whereas Gsg1l, Sfmbt2, Acy3, Polr2a and Ppp1r9a RNA expression levels are affected later, at 12 and 24 months of age. We also analyzed the expression of these 13 genes in human HD and control brain, thereby revealing changes in SLC45A3, PCDH20, ACTN2, DDAH1 and PPP1R9A RNA expression. Further study of these genes may unravel novel pathways contributing to HD pathogenesis. DDBJ/EMBL/GenBank accession no: GSE19677.

Neuroprotective effects of L-carnitine in a transgenic animal model of Huntington's disease

Huntington's disease (HD) is an autosomal dominant inherited disorder, caused by an expanded polyglutamine region of a protein called huntingtin. The excitotoxicity, oxidative damage, mitochondrial dysfunction and altered membrane transport may have important roles in the pathogenesis of HD. L-carnitine plays a role in facilitating the mitochondrial transport of fatty acids, but it also protects the cells from oxidative damage. The aim of our study was to examine the effects of the intraperitoneally administered L-carnitine on the survival, behaviour and immunohistochemical changes in the N171-82Q transgenic mouse model of HD. Following L-carnitine administration the survival was improved by 14.9%. The motor activity was significantly ameliorated as compared with the control transgenic group. The L-carnitine treatment significantly reduced the neuronal loss and the number of neuronal intranuclear aggregates. These results suggest that L-carnitine may exert a neuroprotective effect by decreasing the oxidative damage.

Valproate ameliorates the survival and the motor performance in a transgenic mouse model of Huntington's disease

Huntington's disease (HD) is one of the chronic devastating neurodegenerative disorders. The pathophysiological processes clearly involve both excitotoxicity and reduced gene transcription due to the decreased level of histone acetylation, accompanied by the loss of γ-aminobutyric acidergic (GABAergic) medium-sized spiny neurons in the striatum as a pathological hallmark of HD. Thus, the antiepileptic drug valproate, which has proved GABAergic, antiexcitotoxic and histone deacetylase inhibitor effects, might be of value by exerting a beneficial neuroprotective effect. We have now tested this drug in the N171-82Q transgenic mouse model of HD, following its chronic intraperitoneal administration in a daily dose of 100 mg/kg. Valproate significantly prolonged the survival of the transgenic mice and significantly ameliorated their diminished spontaneous locomotor activity, without exerting any noteworthy side-effect on their behaviour or the striatal dopamine content at the dose administered. The beneficial effect of valproate is probably explained by its complex pharmacological activity. As several previous clinical trials carried out with valproate did not indicate any positive effect in HD, it is worth considering the design of new studies based on a well-planned treatment regime with higher dose, using valproate in monotherapy or in combination therapy with a high number of participating patients.

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.

Neuroprotective effects of probenecid in a transgenic animal model of Huntington’s disease

Huntington's disease (HD) is an autosomal dominantly inherited disorder, caused by an expanded polyglutamine region of a protein called huntingtin. The excitotoxicity, oxidative damage and altered membrane transport may have an important role in the pathogenesis of HD. Probenecid is a non-selective inhibitor of multidrug resistance-associated proteins, but it also inhibits organic anion transporters. In this study, we examined the effects of probenecid on the survival, behaviour and immunohistochemical changes in the N171-82Q transgenic mouse model of HD. After probenecid administration, the duration of survival improved by 35%. The motor activity was significantly ameliorated as compared with the control transgenic group. Probenecid treatment significantly reduced the neuronal loss and the number of neuronal intranuclear aggregates. These results suggest that probenecid may exert a neuroprotective effect by increasing the membrane transport of protective compounds, and/or inhibiting the toxic compounds.