Miro proteins prime mitochondria for Parkin translocation and mitophagy.

The Parkinson's disease-associated protein kinase PINK1 and ubiquitin ligase Parkin coordinate the ubiquitination of mitochondrial proteins, which marks mitochondria for degradation. Miro1, an atypical GTPase involved in mitochondrial trafficking, is one of the substrates tagged by Parkin after mitochondrial damage. Here, we demonstrate that a small pool of Parkin interacts with Miro1 before mitochondrial damage occurs. This interaction does not require PINK1, does not involve ubiquitination of Miro1 and also does not disturb Miro1 function. However, following mitochondrial damage and PINK1 accumulation, this initial pool of Parkin becomes activated, leading to the ubiquitination and degradation of Miro1. Knockdown of Miro proteins reduces Parkin translocation to mitochondria and suppresses mitophagic removal of mitochondria. Moreover, we demonstrate that Miro1 EF-hand domains control Miro1's ubiquitination and Parkin recruitment to damaged mitochondria, and they protect neurons from glutamate-induced mitophagy. Together, our results suggest that Miro1 functions as a calcium-sensitive docking site for Parkin on mitochondria.

Using Rotenone to Model Parkinson's Disease in Mice: A Review of the Role of Pharmacokinetics.

Rotenone is a naturally occurring toxin that inhibits complex I of the mitochondrial electron transport chain. Several epidemiological studies have shown an increased risk of Parkinson's disease (PD) in individuals exposed chronically to rotenone, and it has received great attention for its ability to reproduce many critical features of PD in animal models. Laboratory studies of rotenone have repeatedly shown that it induces in vivo substantia nigra dopaminergic cell loss, a hallmark of PD neuropathology. Additionally, rotenone induces in vivo aggregation of α-synuclein, the major component of Lewy bodies and Lewy neurites found in the brain of PD patients and another hallmark of PD neuropathology. Some in vivo rotenone models also reproduce peripheral signs of PD, such as reduced intestinal motility and peripheral α-synuclein aggregation, both of which are thought to precede classical signs of PD in humans, such as cogwheel rigidity, bradykinesia, and resting tremor. Nevertheless, variability has been noted in cohorts of animals exposed to the same rotenone exposure regimen and also between cohorts exposed to similar doses of rotenone. Low doses, administered chronically, may reproduce PD symptoms and neuropathology more faithfully than excessively high doses, but overlap between toxicity and parkinsonian motor phenotypes makes it difficult to separate if behavior is examined in isolation. Rotenone degrades when exposed to light or water, and choice of vehicle may affect outcome. Rotenone is metabolized extensively in vivo, and choice of route of exposure influences greatly the dose used. However, male rodents may be capable of greater metabolism of rotenone, which could therefore reduce their total body exposure when compared with female rodents. The pharmacokinetics of rotenone has been studied extensively, over many decades. Here, we review these pharmacokinetics and models of PD using this important piscicide.

Phenotype onset in Huntington's disease knock-in mice is correlated with the incomplete splicing of the mutant huntingtin gene.

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expanded CAG repeat within the huntingtin (HTT) gene. The Q140 and HdhQ150 knock-in HD mouse models were generated such that HdhQ150 mice have an expanded CAG repeat inserted into the mouse Htt gene, whereas in the Q140s, mouse exon 1 Htt was replaced with a mutated version of human exon 1. By standardizing mouse strain background, breeding to homozygosity and employing sensitive behavioral tests, we demonstrate that the onset of behavioral phenotypes occurs earlier in the Q140 than the HdhQ150 knock-in mouse models and that huntingtin (HTT) aggregation appears earlier in the striata of Q140 mice. We have previously found that the incomplete splicing of mutant HTT from exon 1 to exon 2 results in the production of a small polyadenylated transcript that encodes the highly pathogenic mutant HTT exon 1 protein. In this report, we have identified a functional consequence of the sequence differences between these two models at the RNA level, in that the level of incomplete splicing, and of the mutant exon 1 HTT protein, are greater in the brains of Q140 mice. While differences in the human and mouse exon 1 HTT proteins (e.g., proline rich sequences) could also contribute to the phenotypic differences, our data indicate that the incomplete splicing of HTT and approaches to lower the levels of the exon 1 HTT transcript should be pursued as therapeutic targets.

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

Huntington's 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 beta-catenin. Huntingtin associates with the beta-catenin destruction complex that ensures its equilibrated degradation. The binding of beta-catenin to the destruction complex is altered in HD, leading to the toxic stabilization of beta-catenin. As a consequence, the beta-transducin repeat-containing protein (beta-TrCP) rescues polyglutamine (polyQ)-huntingtin-induced toxicity in striatal neurons and in a Drosophila model of HD, through the specific degradation of beta-catenin. Finally, the non-steroidal anti-inflammatory drug indomethacin that decreases beta-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 beta-catenin homeostasis in HD is of therapeutic interest.

No Evidence of Sensory Neuropathy in a Traditional Mouse Model of Idiopathic Parkinson's Disease.

Parkinson's disease (PD) is the second-most common neurodegenerative disorder worldwide and is diagnosed based on motor impairments. Non-motor symptoms are also well-recognised in this disorder, and peripheral neuropathy is a frequent but poorly appreciated non-motor sign. Studying how central and peripheral sensory systems are affected can contribute to the development of targeted therapies and deepen our understanding of the pathophysiology of PD. Although the cause of sporadic PD is unknown, chronic exposure to the pesticide rotenone in humans increases the risk of developing the disease. Here, we aimed to investigate whether peripheral neuropathy is present in a traditional model of PD. Mice receiving intrastriatal rotenone showed greatly reduced dopamine terminals in the striatum and a reduction in tyrosine hydroxylase-positive neurons in the Substantia nigra pars compacta and developed progressive motor impairments in hindlimb stepping and rotarod but no change in spontaneous activity. Interestingly, repeated testing using gold-standard protocols showed no change in gut motility, a well-known non-motor symptom of PD. Importantly, we did not observe any change in heat, cold, or touch sensitivity, again based upon repeated testing with well-validated protocols that were statistically well powered. Therefore, this traditional model fails to replicate PD, and our data again reiterate the importance of the periphery to the disorder.

ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.

Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca2+ handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca2+ handling compromises mitochondrial function and affects neuronal health. Loss of ER Ca2+ content and impaired ER-mitochondrial contact sites in the WFS1- or CISD2-deficient neurons is associated with lower IP3R-mediated Ca2+ transfer from ER to mitochondria and decreased mitochondrial Ca2+ uptake. In turn, reduced mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased NADH/NAD+ ratio. The resulting bioenergetic deficit and reductive stress compromise the health of the neurons. Our work also identifies pharmacological targets and compounds that restore Ca2+ homeostasis, enhance mitochondrial function and improve neuronal health.

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 Huntington's 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.

Preclinical trials in Alzheimer's disease: Sample size and effect size for behavioural and neuropathological outcomes in 5xFAD mice.

5xFAD transgenic (TG) mice are used widely in AD preclinical trials; however, data on sample sizes are largely unaddressed. We therefore performed estimates of sample sizes and effect sizes for typical behavioural and neuropathological outcome measures in TG 5xFAD mice, based upon data from single-sex (female) groups. Group-size estimates to detect normalisation of TG body weight to WT littermate levels at 5.5m of age were N = 9-15 depending upon algorithm. However, by 1 year of age, group sizes were small (N = 1 -<6), likely reflecting the large difference between genotypes at this age. To detect normalisation of TG open-field hyperactivity to WT levels at 13-14m, group sizes were also small (N = 6-8). Cued learning in the Morris water maze (MWM) was normal in Young TG mice (5m of age). Mild deficits were noted during MWM spatial learning and memory. MWM reversal learning and memory revealed greater impairment, and groups of up to 22 TG mice were estimated to detect normalisation to WT performance. In contrast, Aged TG mice (tested between 13 and 14m) failed to complete the visual learning (non-spatial) phase of MWM learning, likely due to a failure to recognise the platform as an escape. Estimates of group size to detect normalisation of this severe impairment were small (N = 6-9, depending upon algorithm). Other cognitive tests including spontaneous and forced alternation and novel-object recognition either failed to reveal deficits in TG mice or deficits were negligible. For neuropathological outcomes, plaque load, astrocytosis and microgliosis in frontal cortex and hippocampus were quantified in TG mice aged 2m, 4m and 6m. Sample-size estimates were ≤9 to detect the equivalent of a reduction in plaque load to the level of 2m-old TG mice or the equivalent of normalisation of neuroinflammation outcomes. However, for a smaller effect size of 30%, larger groups of up to 21 mice were estimated. In light of published guidelines on preclinical trial design, these data may be used to provide provisional sample sizes and optimise preclinical trials in 5xFAD TG mice.

A critical window of CAG repeat-length correlates with phenotype severity in the R6/2 mouse model of Huntington's disease.

The R6/2 mouse is the most frequently used model for experimental and preclinical drug trials in Huntington's disease (HD). When the R6/2 mouse was first developed, it carried exon 1 of the huntingtin gene with ~150 cytosine-adenine-guanine (CAG) repeats. The model presented with a rapid and aggressive phenotype that shared many features with the human condition and was particularly similar to juvenile HD. However, instability in the CAG repeat length due to different breeding practices has led to both decreases and increases in average CAG repeat lengths among colonies. Given the inverse relationship in human HD between CAG repeat length and age at onset and to a degree, the direct relationship with severity of disease, we have investigated the effect of altered CAG repeat length. Four lines, carrying ~110, ~160, ~210, and ~310 CAG repeats, were examined using a battery of tests designed to assess the basic R6/2 phenotype. These included electrophysiological properties of striatal medium-sized spiny neurons, motor activity, inclusion formation, and protein expression. The results showed an unpredicted, inverted "U-shaped" relationship between CAG repeat length and phenotype; increasing the CAG repeat length from 110 to 160 exacerbated the R6/2 phenotype, whereas further increases to 210 and 310 CAG repeats greatly ameliorated the phenotype. These findings demonstrate that the expected relationship between CAG repeat length and disease severity observed in humans is lost in the R6/2 mouse model and highlight the importance of CAG repeat-length determination in preclinical drug trials that use this model.

Adipose tissue dysfunction tracks disease progression in two Huntington's disease mouse models.

In addition to the hallmark neurological manifestations of Huntington's disease (HD), weight loss with metabolic dysfunction is often observed in the later stages of disease progression and is associated with poor prognosis. The mechanism for weight loss in HD is unknown. Using two mouse models of HD, the R6/2 transgenic and CAG140 knock-in mouse strains, we demonstrate that adipose tissue dysfunction is detectable at early ages and becomes more pronounced as the disease progresses. Adipocytes acquire a 'de-differentiated' phenotype characterized by impaired expression of fat storage genes. In addition, HD mice exhibit reduced levels of leptin and adiponectin, adipose tissue-derived hormones that regulate food intake and glucose metabolism. Importantly, some of these changes occur prior to weight loss and development of some of the characteristic neurological symptoms. We demonstrate that impaired gene expression and lipid accumulation in adipocytes can be recapitulated by expression of an inducible mutant huntingtin transgene in an adipocyte cell line and that mutant huntingtin inhibits transcriptional activity of the PGC-1alpha co-activator in adipocytes, which may contribute to aberrant gene expression. Thus, our findings indicate that mutant huntingtin has direct detrimental effects in cell types other than neurons. The results also indicate that circulating adipose-tissue-derived hormones may be accessible markers for HD prognosis and progression and suggest that adipose tissue may be a useful therapeutic target to improve standard of life for HD patients.

Early Intervention and Lifelong Treatment with GLP1 Receptor Agonist Liraglutide in a Wolfram Syndrome Rat Model with an Emphasis on Visual Neurodegeneration, Sensorineural Hearing Loss and Diabetic Phenotype.

Wolfram syndrome (WS), also known as a DIDMOAD (diabetes insipidus, early-onset diabetes mellitus, optic nerve atrophy and deafness) is a rare autosomal disorder caused by mutations in the Wolframin1 (WFS1) gene. Previous studies have revealed that glucagon-like peptide-1 receptor agonist (GLP1 RA) are effective in delaying and restoring blood glucose control in WS animal models and patients. The GLP1 RA liraglutide has also been shown to have neuroprotective properties in aged WS rats. WS is an early-onset, chronic condition. Therefore, early diagnosis and lifelong pharmacological treatment is the best solution to control disease progression. Hence, the aim of this study was to evaluate the efficacy of the long-term liraglutide treatment on the progression of WS symptoms. For this purpose, 2-month-old WS rats were treated with liraglutide up to the age of 18 months and changes in diabetes markers, visual acuity, and hearing sensitivity were monitored over the course of the treatment period. We found that treatment with liraglutide delayed the onset of diabetes and protected against vision loss in a rat model of WS. Therefore, early diagnosis and prophylactic treatment with the liraglutide may also prove to be a promising treatment option for WS patients by increasing the quality of life.

Mitochondrial transport proteins RHOT1 and RHOT2 serve as docking sites for PRKN-mediated mitophagy.

The Parkinson disease-associated proteins PINK1 and PRKN coordinate the ubiquitination of mitochondrial outer membrane proteins to tag them either for degradation or for autophagic clearance of the mitochondrion. The proteins include the mitochondrial trafficking proteins RHOT1 and RHOT2, the removal of which may be required for immobilization of mitochondria prior to mitophagy. Here, we demonstrate that RHOT1 and RHOT2 are not only substrates for PINK1-PRKN-dependent degradation but that they also play an active role in the process of mitophagy. RHOT1, and likely also RHOT2, may act as a docking site for inactive PRKN prior to mitochondrial damage, thus keeping PRKN in close proximity to its potential substrates and thereby facilitating mitophagy. We also show that RHOT1 functions as a calcium-sensing docking site for PRKN, and we suggest that calcium binding to RHOT is a key step in the calcium-dependent activation of mitophagy machinery.

Neural cell adhesion molecule Negr1 deficiency in mouse results in structural brain endophenotypes and behavioral deviations related to psychiatric disorders.

Neuronal growth regulator 1 (NEGR1) belongs to the immunoglobulin (IgLON) superfamily of cell adhesion molecules involved in cortical layering. Recent functional and genomic studies implicate the role of NEGR1 in a wide spectrum of psychiatric disorders, such as major depression, schizophrenia and autism. Here, we investigated the impact of Negr1 deficiency on brain morphology, neuronal properties and social behavior of mice. In situ hybridization shows Negr1 expression in the brain nuclei which are central modulators of cortical-subcortical connectivity such as the island of Calleja and the reticular nucleus of thalamus. Brain morphological analysis revealed neuroanatomical abnormalities in Negr1-/- mice, including enlargement of ventricles and decrease in the volume of the whole brain, corpus callosum, globus pallidus and hippocampus. Furthermore, decreased number of parvalbumin-positive inhibitory interneurons was evident in Negr1-/- hippocampi. Behaviorally, Negr1-/- mice displayed hyperactivity in social interactions and impairments in social hierarchy. Finally, Negr1 deficiency resulted in disrupted neurite sprouting during neuritogenesis. Our results provide evidence that NEGR1 is required for balancing the ratio of excitatory/inhibitory neurons and proper formation of brain structures, which is prerequisite for adaptive behavioral profiles. Therefore, Negr1-/- mice have a high potential to provide new insights into the neural mechanisms of neuropsychiatric disorders.

Wfs1- deficient rats develop primary symptoms of Wolfram syndrome: insulin-dependent diabetes, optic nerve atrophy and medullary degeneration.

Wolfram syndrome (WS) is a rare autosomal-recessive disorder that is caused by mutations in the WFS1 gene and is characterized by juvenile-onset diabetes, optic atrophy, hearing loss and a number of other complications. Here, we describe the creation and phenotype of Wfs1 mutant rats, in which exon 5 of the Wfs1 gene is deleted, resulting in a loss of 27 amino acids from the WFS1 protein sequence. These Wfs1-ex5-KO232 rats show progressive glucose intolerance, which culminates in the development of diabetes mellitus, glycosuria, hyperglycaemia and severe body weight loss by 12 months of age. Beta cell mass is reduced in older mutant rats, which is accompanied by decreased glucose-stimulated insulin secretion from 3 months of age. Medullary volume is decreased in older Wfs1-ex5-KO232 rats, with the largest decreases at the level of the inferior olive. Finally, older Wfs1-ex5-KO232 rats show retinal gliosis and optic nerve atrophy at 15 months of age. Electron microscopy revealed axonal degeneration and disorganization of the myelin in the optic nerves of older Wfs1-ex5-KO232 rats. The phenotype of Wfs1-ex5-KO232 rats indicates that they have the core symptoms of WS. Therefore, we present a novel rat model of WS.

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

Genetic mouse models based on identification of genes that cause Huntington's and Parkinson's 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 Huntington's disease models because the disorder involves a single gene that was identified over ten years ago; genetic mutations causing Parkinson's 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.

Huntington's 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.

BECN1 is involved in the initiation of mitophagy: it facilitates PARK2 translocation to mitochondria.

The autophagy protein BECN1/Beclin 1 is known to play a central role in autophagosome formation and maturation. The results presented here demonstrate that BECN1 interacts with the Parkinson disease-related protein PARK2. This interaction does not require PARK2 translocation to mitochondria and occurs mostly in cytosol. However, our results suggest that BECN1 is involved in PARK2 translocation to mitochondria because loss of BECN1 inhibits CCCP- or PINK1 overexpression-induced PARK2 translocation. Our results also demonstrate that the observed PARK2-BECN1 interaction is functionally important. Measurements of the level of MFN2 (mitofusin 2), a PARK2 substrate, demonstrate that depletion of BECN1 prevents PARK2 translocation-induced MFN2 ubiquitination and loss. BECN1 depletion also rescues the MFN2 loss-induced suppression of mitochondrial fusion. In sum, our results demonstrate that BECN1 interacts with PARK2 and regulates PARK2 translocation to mitochondria as well as PARK2-induced mitophagy prior to autophagosome formation.

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

Huntington's 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.

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

BACKGROUND: No disease modifying treatment currently exists for Huntington's 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. RESULTS: KI 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 curcumin's 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 Alzheimer's disease. CONCLUSION: Together 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.

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.