Miriam A. Hickey

Extensive early motor and non-motor behavioral deficits are followed by striatal neuronal loss in knock-in Huntington's disease mice.

Huntingtons disease is a neurodegenerative disorder, caused by an elongation of CAG repeats in the huntingtin gene. Mice with an insertion of an expanded polyglutamine repeat in the mouse huntingtin gene (knock-in mice) most closely model the disease because the mutation is expressed in the proper genomic and protein context. However, few knock-in mouse lines have been extensively characterized and available data suggest marked differences in the extent and time course of their behavioral and pathological phenotype. We have previously described behavioral anomalies in the open field as early as 1 month of age, followed by the appearance at 2 months of progressive huntingtin neuropathology, in a mouse carrying a portion of human exon 1 with approximately 140 CAG repeats inserted into the mouse huntingtin gene. Here we extend these observations by showing that early behavioral anomalies exist in a wide range of motor (climbing, vertical pole, rotarod, and running wheel performance) and non-motor functions (fear conditioning and anxiety) starting at 1-4 months of age, and are followed by progressive gliosis and decrease in dopamine and cyclic AMP-regulated phosphoprotein with molecular weight 32 kDa (DARPP32) (12 months) and a loss of striatal neurons at 2 years. At this age, mice also present striking spontaneous behavioral deficits in their home cage. The data show that this line of knock-in mice reproduces canonical characteristics of Huntingtons disease, preceded by deficits which may correspond to the protracted pre-manifest phase of the disease in humans. Accordingly, they provide a useful model to elucidate early mechanisms of pathophysiology and the progression to overt neurodegeneration.

Genetic mouse models of Huntington's and Parkinson's diseases: illuminating but imperfect

Genetic mouse models based on identification of genes that cause Huntingtons and Parkinsons diseases have revolutionized understanding of the mechanistic pathophysiological progression of these disorders. These models allow the earliest manifestations of the diseases to be identified, and they display behavioral, neuropathological and electrophysiological deficits that can be followed over time in mechanistic and drug studies. An intriguing feature is that they do not reproduce the relatively selective and massive cell loss characterizing the human diseases. There is more information on Huntingtons disease models because the disorder involves a single gene that was identified over ten years ago; genetic mutations causing Parkinsons disease are rare and were discovered more recently, and models of the disease have been generated only within the past few years.

Apoptosis in Huntington's disease.

Huntingtons disease (HD) is an autosomal dominant, fatal disorder. Patients display increasing motor, psychiatric and cognitive impairment and at autopsy, late-stage patient brains show extensive striatal (caudate and putamen), pallidal and cortical atrophy. The initial and primary target of degeneration in HD is the striatal medium spiny GABAergic neuron, and by end stages of the disease up to 95% of these neurons are lost [J. Neuropathol. Exp. Neurol. 57 (1998) 369]. The disease is caused by an elongation of a polyglutamine tract in the N-terminal of the huntingtin gene, but it is not known how this mutation leads to such extensive, but selective, cell death [Cell 72 (1993) 971]. There is substantial evidence from in vitro studies that connects apoptotic pathways and apoptosis with the mutant protein, and theories linking apoptosis to neuronal death in HD have existed for several years. Despite this, evidence of apoptotic neuronal death in HD is scarce. It may be that the processes involved in apoptosis, rather than apoptosis per se, are more important for HD pathogenesis. Upregulation of the proapoptotic proteins could lead to cleavage of huntingtin and as recent data has shown, the consequent toxic fragment may itself elicit toxic effects on the cell by disrupting transcription. In addition, the increased levels of proapoptotic proteins could contribute to slowly developing cell death in HD, selective for the striatal medium spiny GABAergic neurons and later spreading to other areas. Here we review the evidence supporting these mechanisms of pathogenesis in HD.

Mutant huntingtin-impaired degradation of β-catenin causes neurotoxicity in Huntington's disease

Huntingtons disease (HD) is a fatal neurodegenerative disorder causing selective neuronal death in the brain. Dysfunction of the ubiquitin–proteasome system may contribute to the disease; however, the exact mechanisms are still unknown. We report here a new pathological mechanism by which mutant huntingtin specifically interferes with the degradation of β‐catenin. Huntingtin associates with the β‐catenin destruction complex that ensures its equilibrated degradation. The binding of β‐catenin to the destruction complex is altered in HD, leading to the toxic stabilization of β‐catenin. As a consequence, the β‐transducin repeat‐containing protein (β‐TrCP) rescues polyglutamine (polyQ)‐huntingtin‐induced toxicity in striatal neurons and in a Drosophila model of HD, through the specific degradation of β‐catenin. Finally, the non‐steroidal anti‐inflammatory drug indomethacin that decreases β‐catenin levels has a neuroprotective effect in a neuronal model of HD and in Drosophila and increases the lifespan of HD flies. We thus suggest that restoring β‐catenin homeostasis in HD is of therapeutic interest.

Improvement of neuropathology and transcriptional deficits in CAG 140 knock-in mice supports a beneficial effect of dietary curcumin in Huntington's disease

BackgoundNo disease modifying treatment currently exists for Huntingtons disease (HD), a fatal neurodegenerative disorder characterized by the formation of amyloid-like aggregates of the mutated huntingtin protein. Curcumin is a naturally occurring polyphenolic compound with Congo red-like amyloid binding properties and the ability to cross the blood brain barrier. CAG140 mice, a knock-in (KI) mouse model of HD, display abnormal aggregates of mutant huntingtin and striatal transcriptional deficits, as well as early motor, cognitive and affective abnormalities, many months prior to exhibiting spontaneous gait deficits, decreased striatal volume, and neuronal loss. We have examined the ability of life-long dietary curcumin to improve the early pathological phenotype of CAG140 mice.ResultsKI mice fed a curcumin-containing diet since conception showed decreased huntingtin aggregates and increased striatal DARPP-32 and D1 receptor mRNAs, as well as an amelioration of rearing deficits. However, similar to other antioxidants, curcumin impaired rotarod behavior in both WT and KI mice and climbing in WT mice. These behavioral effects were also noted in WT C57Bl/6 J mice exposed to the same curcumin regime as adults. However, neither locomotor function, behavioral despair, muscle strength or food utilization were affected by curcumin in this latter study. The clinical significance of curcumins impairment of motor performance in mice remains unclear because curcumin has an excellent blood chemistry and adverse event safety profile, even in the elderly and in patients with Alzheimers disease.ConclusionTogether with this clinical experience, the improvement in several transgene-dependent parameters by curcumin in our study supports a net beneficial effect of dietary curcumin in HD.

Striatal atrophy and dendritic alterations in a knock-in mouse model of Huntington's disease

Huntingtons disease (HD) is a progressive neurodegenerative disease characterized by progressive atrophy of the striatum, cerebral cortex, and white matter tracks. Major pathological hallmarks of HD include neuronal loss, primarily in the striatum, and dendritic anomalies in surviving striatal neurons. Although many mouse models of HD have been generated, their success at reproducing all pathological features of the disease is not fully known. Previously, we demonstrated extensive striatal neuronal loss and striatal atrophy at 20-26 months of age in a knock-in (KI) mouse model of HD. To further investigate this model, which carries a human exon 1 with ∼119 CAG repeats inserted into the mouse gene (initially 140 repeats), we have examined whether these mice exhibit the atrophy and neuronal anomalies characteristic of HD. Stereological analyses revealed no changes in the striatal volume of male and female homozygote mice at 4 months, however striatal atrophy was already present at 12 months in both sexes. Analysis of cortical and corpus callosum volume in male homozygotes revealed a loss in corpus callosum volume by 20-26 months. At this later age, the surviving striatal neurons displayed extensive loss of spines in distal branch orders that affected both immature and mature spines. Mirroring late stage HD striatal neuronal morphology, the striatal neurons at this late age also showed reduced dendritic complexity, as revealed by Sholl analysis. Tyrosine hydroxylase immunoreactivity was also decreased in the striatum of 20-26 month old KI mice, suggesting an alteration in striatal inputs. These data further indicate that CAG140 homozygote KI mice exhibit HD-like pathological features and are a useful model to test the effects of early and/or sustained administration of novel neuroprotective treatments.

Rescuing the Corticostriatal Synaptic Disconnection in the R6/2 Mouse Model of Huntington's Disease: Exercise, Adenosine Receptors and Ampakines.

In the R6/2 mouse model of Huntington’s disease (HD) we examined the effects of a number of behavioral and pharmacological manipulations aimed at rescuing the progressive loss of synaptic communication between cerebral cortex and striatum. Two cohorts of transgenic mice with ~110 and 210 CAG repeats were utilized. Exercise prevented the reduction in striatal medium-sized spiny neuron membrane capacitance but did not reestablish synaptic communication. Activation of adenosine A2A type receptors renormalized postsynaptic activity to some extent. Finally, the ampakine Cx614, which has been shown to prevent α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor desensitization, slow deactivation, and facilitate glutamate release, induced significant increases in synaptic activity, albeit the effect was somewhat reduced in fully symptomatic, compared to control mice. With some limitations, each of these strategies can be used to delay and partially rescue phenotypic progression of HD in this model.

Evidence for behavioral benefits of early dietary supplementation with CoEnzymeQ10 in a slowly progressing mouse model of Huntington's disease.

Controversies surround the usefulness of Coenzyme Q10 (CoQ10) in Huntingtons disease (HD), an autosomal dominant, fatal, neurodegenerative disease with no cure or disease modifying treatment. CoQ10, an endogenous substrate for electron transport and an anti-oxidant, has been shown in some but not all studies to improve symptoms and survival in mouse models of HD. Previous studies have been conducted in fast-progressing models that better mimic the juvenile forms of HD than the much more common middle-age onset form, possibly accounting for mixed results. Establishing the usefulness of CoQ10 to alter HD disease course in a model that better recapitulates the progressive features of the human disorder is important because clinical trials of CoQ10, which is safe and well tolerated, are being planned in patients. The CAG140 knock-in (KI) mouse model of HD in which an expanded (approximately 120) CAG repeat is inserted in the mouse gene provides a model of the mutation in the proper genomic and protein context. These mice display progressive motor, cognitive and emotional anomalies, transcriptional disturbances and late striatal degeneration. Homozygote mutant CAG140 KI mice and wild-type littermates were fed CoQ10 (0.2%, 0.6%) in chow, and behavioral and pathological markers of disease were examined. CoQ10 improved early behavioral deficits and normalized some transcriptional deficits without altering huntingtin aggregates in striatum. The lower dose (0.2%) was more beneficial than 0.6%. Similar to previous studies, this low dose also induced deleterious effects in open field and rotarod in WT mice, however these effects are of unclear clinical significance in view of the excellent safety profile of CoQ10 in humans. These data confirm that CoQ10 may be beneficial in HD but suggest that maximum benefit may be observed when treatment is begun at early stages of the disease and that dosage may be critical.

Mouse Models of Mental Illness and Neurological Disease: Huntington s Disease

Publisher Summary Huntingtons disease (HD) is an autosomal dominant, genetic disorder that causes progressive degeneration in the central nervous system (CNS). Patients exhibit inexorable decline in motor control and cognitive function, in addition to psychiatric disturbances. The disease, which affects up to 1 in 10,000 people worldwide, is caused by the expansion of a trinucleotide cytosine-adenineguanine (CAG) repeat within exon 1 of the HD gene. Disease onset is usually in midlife and progresses towards death within 20 years. Although some symptoms may be treated, there are currently no effective disease-modifying agents. Animal models of HD have provided insights into the pathogenic mechanisms underlying the disease and have been used widely for preclinical assessment of therapeutic strategies. In HD, several mechanisms are likely implicated in causing neurodegeneration, including metabolic compromise, oxidative stress, excitotoxicity, and alterations in gene expression. Models of HD in vitro and in vivo have made a significant contribution to the current understanding of HD pathogenesis. Animal models of HD may be broadly divided into two types: those generated by neurotoxic chemical lesions of the striatum and those generated by expression of fragments or full-length mutant htt. Prior to the identification of the underlying genetic mutation in HD, animal models that mimic striatal neuronal cell loss were generated by excitotoxic lesioning of the striatum or metabolic impairment via mitochondrial disruption. Developments in recombinant virus vector technology have facilitated the generation of animal models of HD based on transfer of mutant htt expression constructs into the somatic brain cells of experimental animals. A main purpose for generating mouse models of diseases is to provide a tool for preclinical drug testing of potential therapies. There is currently no treatment that delays onset, slows progression, or reverses the course of HD.Publisher Summary Huntingtons disease (HD) is an autosomal dominant, genetic disorder that causes progressive degeneration in the central nervous system (CNS). Patients exhibit inexorable decline in motor control and cognitive function, in addition to psychiatric disturbances. The disease, which affects up to 1 in 10,000 people worldwide, is caused by the expansion of a trinucleotide cytosine-adenineguanine (CAG) repeat within exon 1 of the HD gene. Disease onset is usually in midlife and progresses towards death within 20 years. Although some symptoms may be treated, there are currently no effective disease-modifying agents. Animal models of HD have provided insights into the pathogenic mechanisms underlying the disease and have been used widely for preclinical assessment of therapeutic strategies. In HD, several mechanisms are likely implicated in causing neurodegeneration, including metabolic compromise, oxidative stress, excitotoxicity, and alterations in gene expression. Models of HD in vitro and in vivo have made a significant contribution to the current understanding of HD pathogenesis. Animal models of HD may be broadly divided into two types: those generated by neurotoxic chemical lesions of the striatum and those generated by expression of fragments or full-length mutant htt. Prior to the identification of the underlying genetic mutation in HD, animal models that mimic striatal neuronal cell loss were generated by excitotoxic lesioning of the striatum or metabolic impairment via mitochondrial disruption. Developments in recombinant virus vector technology have facilitated the generation of animal models of HD based on transfer of mutant htt expression constructs into the somatic brain cells of experimental animals. A main purpose for generating mouse models of diseases is to provide a tool for preclinical drug testing of potential therapies. There is currently no treatment that delays onset, slows progression, or reverses the course of HD.

Mouse Models of Mental Illness and Neurological Disease

Publisher Summary Huntingtons disease (HD) is an autosomal dominant, genetic disorder that causes progressive degeneration in the central nervous system (CNS). Patients exhibit inexorable decline in motor control and cognitive function, in addition to psychiatric disturbances. The disease, which affects up to 1 in 10,000 people worldwide, is caused by the expansion of a trinucleotide cytosine-adenineguanine (CAG) repeat within exon 1 of the HD gene. Disease onset is usually in midlife and progresses towards death within 20 years. Although some symptoms may be treated, there are currently no effective disease-modifying agents. Animal models of HD have provided insights into the pathogenic mechanisms underlying the disease and have been used widely for preclinical assessment of therapeutic strategies. In HD, several mechanisms are likely implicated in causing neurodegeneration, including metabolic compromise, oxidative stress, excitotoxicity, and alterations in gene expression. Models of HD in vitro and in vivo have made a significant contribution to the current understanding of HD pathogenesis. Animal models of HD may be broadly divided into two types: those generated by neurotoxic chemical lesions of the striatum and those generated by expression of fragments or full-length mutant htt. Prior to the identification of the underlying genetic mutation in HD, animal models that mimic striatal neuronal cell loss were generated by excitotoxic lesioning of the striatum or metabolic impairment via mitochondrial disruption. Developments in recombinant virus vector technology have facilitated the generation of animal models of HD based on transfer of mutant htt expression constructs into the somatic brain cells of experimental animals. A main purpose for generating mouse models of diseases is to provide a tool for preclinical drug testing of potential therapies. There is currently no treatment that delays onset, slows progression, or reverses the course of HD.Publisher Summary Huntingtons disease (HD) is an autosomal dominant, genetic disorder that causes progressive degeneration in the central nervous system (CNS). Patients exhibit inexorable decline in motor control and cognitive function, in addition to psychiatric disturbances. The disease, which affects up to 1 in 10,000 people worldwide, is caused by the expansion of a trinucleotide cytosine-adenineguanine (CAG) repeat within exon 1 of the HD gene. Disease onset is usually in midlife and progresses towards death within 20 years. Although some symptoms may be treated, there are currently no effective disease-modifying agents. Animal models of HD have provided insights into the pathogenic mechanisms underlying the disease and have been used widely for preclinical assessment of therapeutic strategies. In HD, several mechanisms are likely implicated in causing neurodegeneration, including metabolic compromise, oxidative stress, excitotoxicity, and alterations in gene expression. Models of HD in vitro and in vivo have made a significant contribution to the current understanding of HD pathogenesis. Animal models of HD may be broadly divided into two types: those generated by neurotoxic chemical lesions of the striatum and those generated by expression of fragments or full-length mutant htt. Prior to the identification of the underlying genetic mutation in HD, animal models that mimic striatal neuronal cell loss were generated by excitotoxic lesioning of the striatum or metabolic impairment via mitochondrial disruption. Developments in recombinant virus vector technology have facilitated the generation of animal models of HD based on transfer of mutant htt expression constructs into the somatic brain cells of experimental animals. A main purpose for generating mouse models of diseases is to provide a tool for preclinical drug testing of potential therapies. There is currently no treatment that delays onset, slows progression, or reverses the course of HD.