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International audience; Objective: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder associated with motor, psychiatric and cognitive deterioration over time. To date, Continuous Electrical Neuromodulation (CEN) of the globus pallidus internus (GPi) has been reported to improve chorea but little is known about cognitive progression in these patients. We propose to examine CEN impact on expected cognitive decline throughout long-term neuropsychological assessment of a cohort of HD patients.Method: 13 consecutive HD patients underwent GPi neuromodulation between January 2008 and February 2019. Over a 5-year follow-up period, they received systematic pre- and post-operative assessment according to the existing protocol in our unit. The main outcome measure was the total score obtained on the Mattis Dementia Rating Scale (MDRS) as an indicator of global cognitive function.Results: Chorea decreased in all patients postoperatively with a mean improvement of 56% despite disease progression over time, according to previous studies. Moreover we found that the global cognitive profile of HD patients treated with CEN was stable during the first 3 years of treatment.Conclusion: We report an unexpected positive influence of GPi continuous electrical neuromodulation on the progression of global cognitive functioning in operated HD patients. This is the most important group of patients treated with this method to our knowledge whatever the sample size remains small. This result provides promising evidence of GPi-CEN efficacy not only in reducing chorea, but also in delaying cognitive decline in HD patients operated at an early stage of the disease.

Non-Invasive Prenatal Diagnosis (NIPD), based on the analysis of circulating cell-free fetal DNA (cff-DNA), is successfully implemented for an increasing number of monogenic diseases. However, technical issues related to cff-DNA characteristics remain, and not all mutations can be screened with this method, particularly triplet expansion mutations that frequently concern prenatal diagnosis requests. The objective of this study was to develop an approach to isolate and analyze Circulating Trophoblastic Fetal Cells (CFTCs) for NIPD of monogenic diseases caused by triplet repeat expansion or point mutations. We developed a method for CFTC isolation based on DEPArray sorting and used Huntington’s disease as the clinical model for CFTC-based NIPD. Then, we investigated whether CFTC isolation and Whole Genome Amplification (WGA) could be used for NIPD in couples at risk of transmitting different monogenic diseases. Our data show that the allele drop-out rate was 3-fold higher in CFTCs than in maternal cells processed in the same way. Moreover, we give new insights into CFTCs by compiling data obtained by extensive molecular testing by microsatellite multiplex PCR genotyping and by WGA followed by mini-exome sequencing. CFTCs appear to be often characterized by a random state of genomic degradation.

International audience; Background: Physical exercise improves neurological conditions, but adherence is hard to establish. Dance might be a promising alternative; however, since patients with Huntington's disease (HD) suffer from rhythmic movement execution deficits, any metric dance practice must be avoided.Objective: Here we asked, if contemporary dance, a lyrical dance form, practiced for two hours per week over five months, might improve motor function, neuropsychiatric variables, cognition and brain volume of HD patients.Methods: Nineteen patients aged between 43 and 78 years with mild to moderate HD (TFC range 7-13, UHDRS motor score range 3-58) participated in this randomized, controlled pilot study (NCT 01842919). The primary outcome measure was total motor score. Secondary outcome measures were differences in brain structure, cognitive function, neuropsychiatric variables, apathy and quality of life. A semi-structured interview assessed participants' experiences.Results: Adherence to dance classes was very good. All participants completed 5 months of dance practice. Motor impairment (median [IQR] decreased from 28[6-51] to 27[7-33] for the dance group compared to an increase of 19[13-35] - 25[14-42] for usual care, Z = -2.44, p = 0.015). No other behavioral measures showed any changes.Brain volume increased in the medial superior parietal and paracentral lobule, in line with compensatory structural brain changes in areas supporting spatial and somatosensory processing. These changes were also reflected in patients' reports that contemporary dance altered the way they "felt and lived in their bodies".Conclusions: Contemporary dance practice, through work on spatial and bodily representations, helps improve motor function in HD patients.

International audience; Huntington disease (HD) is a paradigmatic autosomal-dominant adult-onset neurodegenerative disease. Since the identification of an abnormal expansion of a trinucleotide repeat tract in the huntingtin gene as the underlying genetic defect, a broad range of transgenic animal models of the disease has become available and these have helped to unravel the relevant molecular pathways in unprecedented detail. Of note, some of the most informative of these models develop thermoregulatory defects such as hypothermia, problems with adaptive thermogenesis, and an altered circadian temperature rhythm. Both central, e.g., in the hypothalamus and peripheral, i.e., the brown adipose tissue and skeletal muscle, problems contribute to the phenotype. Importantly, these structures and pathways are also affected in human HD. Yet, currently the evidence for bona fide thermodysregulation in human HD patients remains anecdotal. This may be due to a lack of reliable tools for monitoring body temperature in an outpatient setting. Regardless, study of the temperature phenotype has contributed to the identification of unexpected molecular targets, such as the PGC-1α pathway.

Huntington disease (HD) is a neurodegenerative disease of genetic origin, fewer than 10% of patients present before the age of 20. This study based about 37 children and adolescents born in family affected by HD, and admitted to the juvenile HD (JHD) Central Ward from 2005 to 2017. We studied the reason of consultation, the initial symptomatology of JHD, secondary difficulties linked to parental disease and approach to diagnose at this age. 18 out of 37 patients develop symptoms suggestive of JHD: none of them present the suggestive triad of clinical characteristics of HD that are present in adult, their initial symptomatology’s low rate specificity make the approach to diagnose more complicated. In fact, the genetic testing can be theoretically unfavorable in 50% of the cases, and do not allow differentiating the pre-symptomatic and predictive genetic testing from symptomatic patient’s testing. At this age, it is therefore necessary to discuss many differential diagnoses and we believe that neuropsychological assessments and MRI are essential. We were surprised by numbers of patients who have troubles in learning (neurodevelopmental disorders) (66%) and scoliosis (27%). For 17 patients out of 37, their symptomatology is secondary to dysfunction created by parental disease and for 2 patients, another disease were diagnosed. This study shows the difficulty in JHD diagnosis at the beginning of the disease and complexity to approach and diagnose. Thus, the direction of genetic testing in minors need to be discussed with the child and his or her parents, while respecting the legislation.; La maladie de Huntington (MH), maladie neurodégénérative d’origine génétique, dominante, ne débute avant l’âge de 20 ans que chez 10% des patients. Cette étude rétrospective concerne 37 enfants et adolescents nés dans une famille touchée par la MH et adressés au CRMR MH pédiatrique entre 2005 et 2017. Nous avons étudié les motifs de consultation, la symptomatologie initiale des formes juvéniles, les difficultés « secondaires » liés à la présence de maladie parentale, et la démarche diagnostique spécifique à cet âge. 18/37 patients sont atteints d’une MH juvénile : aucun ne présentait la triade symptomatique évocatrice décrite chez l’adulte, leur symptomatologie initiale était souvent peu spécifique rendant la démarche diagnostique complexe. Le test moléculaire, théoriquement défavorable chez 50% d’entre eux, ne permet pas de différencier formellement les formes symptomatiques des formes pré-symptomatiques. A cet âge, il est donc nécessaire de discuter de nombreux diagnostics différentiels et nous pensons que les évaluations neuropsychologiques et l’IRM sont indispensables. Nous avons été frappés par la fréquence de troubles neurodéveloppementaux (66%) et des scolioses (27%) dans ces formes juvéniles de MH. Chez 17/37 enfants la symptomatologie est considérée comme secondaire aux dysfonctionnements engendrés par la pathologie parentale et chez 2/37 une autre étiologie a été identifiée. Ce travail illustre les difficultés du diagnostic de MH juvénile au début de la maladie et la complexité de la démarche diagnostique. Ainsi l’indication du test génétique à l’âge pédiatrique nécessite d’être discutée en équipe, avec l’enfant et ses parents, tout en respectant la législation.

International audience; Huntington's disease (HD) is a polyglutamine (polyQ) disease caused by an expanded CAG tract within the coding region of Huntingtin protein. Mutant Huntingtin (mHtt) is ubiquitously expressed, abundantly in neurons but also significantly in glial cells. Neuron-intrinsic mechanism and alterations in glia-to-neuron communication both contribute to the neuronal dysfunction and death in HD pathology. However, it remains to be determined the role of glial cells in HD pathogenesis. In recent years, development of Drosophila models facilitated the dissection of the cellular and molecular events in polyQ-related diseases. By using genetic approaches in Drosophila, we manipulated the expression levels of mitochondrial uncoupling proteins (UCPs) that regulate production of both ATP and reactive oxygen species in mitochondria. We discovered that enhanced levels of UCPs alleviated the HD phenotype when mHtt was selectively expressed in glia, including defects in locomotor behavior and early death of Drosophila. In contrast, UCPs failed to prevent the HD toxicity in neurons. Increased oxidative stress defense was found to rescue neuron but not glia-induced pathology. Evidence is now emerging that UCPs are fundamental to adapt the energy metabolism in order to meet the metabolic demand. Thus, we propose that UCPs are glioprotective by rescuing energy-dependent functions in glia that are challenged by mHtt. In support of this, increasing glucose entry in glia was found to alleviate glia-induced pathology. Altogether, our data emphasize the importance of energy metabolism in the glial alterations in HD and may lead to a new therapeutic avenue.

International audience; Mitochondrial dysfunctions have been implicated in the cellular processes underlying several neurodegenerative disorders affecting the basal ganglia. These include Huntington's chorea and Parkinson's disease, two highly debilitating motor disorders for which recent research has also involved gene mutation linked to mitochondrial deficits. Experimental models of basal ganglia diseases have been developed by using toxins able to disrupt mitochondrial function: these molecules act by selectively inhibiting mitochondrial respiratory complexes, uncoupling cellular respiration. This in turn leads to oxidative stress and energy deficit that trigger critical downstream mechanisms, ultimately resulting in neuronal vulnerability and loss. Here we review the molecular and cellular downstream effects triggered by mitochondrial dysfunction, and the different experimental models that are obtained by the administration of selective mitochondrial toxins or by the expression of mutant genes.

International audience; Sequence-specific nucleated protein aggregation is closely linked to the pathogenesis of most neurodegenerative diseases and constitutes the molecular basis of prion formation. Here we report that fibrillar polyglutamine peptide aggregates can be internalized by mammalian cells in culture where they gain access to the cytosolic compartment and become co-sequestered in aggresomes together with components of the ubiquitin-proteasome system and cytoplasmic chaperones. Remarkably, these internalized fibrillar aggregates are able to selectively recruit soluble cytoplasmic proteins with which they share homologous but not heterologous amyloidogenic sequences, and to confer a heritable phenotype on cells expressing the homologous amyloidogenic protein from a chromosomal locus.

International audience; Cleavage of mutant huntingtin (HTT) is an essential process in Huntington's disease (HD), an inherited neurodegenerative disorder. Cleavage generates N-ter fragments that contain the polyQ stretch and whose nuclear toxicity is well established. However, the functional defects induced by cleavage of full-length HTT remain elusive. Moreover, the contribution of non-polyQ C-terminal fragments is unknown. Using time- and site-specific control of full-length HTT proteolysis, we show that specific cleavages are required to disrupt intramolecular interactions within HTT and to cause toxicity in cells and flies. Surprisingly, in addition to the canonical pathogenic N-ter fragments, the C-ter fragments generated, that do not contain the polyQ stretch, induced toxicity via dilation of the endoplasmic reticulum (ER) and increased ER stress. C-ter HTT bound to dynamin 1 and subsequently impaired its activity at ER membranes. Our findings support a role for HTT on dynamin 1 function and ER homoeostasis. Proteolysis-induced alteration of this function may be relevant to disease.

International audience; Huntington's disease is characterized by neuronal loss throughout the disease course. Voxel-based morphometry studies have reported reductions in gray matter concentration (GMC) in many brain regions in patients with Huntington. The description of the time course of gray matter loss may help to identify some evolution markers. Here, we conducted a meta-analysis of voxel-based morphometry studies of Huntington's disease to describe the evolution of brain gray matter loss. A systematic search led to the inclusion of 11 articles on Huntington's disease (297 patients and 205 controls). We extracted data from patients with preclinical Huntington, patients with clinical Huntington, and controls. Finally, anatomical likelihood estimation analyses were conducted to identify GMC changes between preclinical patients and controls, between clinical patients and controls, and between preclinical and clinical patients. Preclinical patients exhibited gray matter loss in the left basal ganglia and the prefrontal cortex. Clinical patients had bilateral gray matter loss in the basal ganglia, the prefrontal cortex, and the insula. The left striatum was smaller in clinical patients than in preclinical patients. Neurodegenerative processes associated with Huntington's disease, as assessed by GMC reduction, begin in the left hemisphere and extend to the contralateral hemisphere throughout the inexorable course of the disease. Changes in gray matter, especially the volumetric side ratio of the striatum, could represent a relevant biomarker for characterizing the different progression stages of the disease.

International audience; An apparatus that combines dynamic light scattering and Thioflavin T fluorescence detection is used to simultaneously probe fibril formation in polyglutamine peptides, the aggregating subunit associated with Huntington's disease, in vitro. Huntington's disease is a neurodegenerative disorder in a class of human pathologies that includes Alzheimer's and Parkinson's disease. These pathologies are all related by the propensity of their associated protein or polypeptide to form insoluble, β-sheet rich, amyloid fibrils. Despite the wide range of amino acid sequence in the aggregation prone polypeptides associated with these diseases, the resulting amyloids display strikingly similar physical structure, an observation which suggests a physical basis for amyloid fibril formation. Thioflavin T fluorescence reports β-sheet fibril content while dynamic light scattering measures particle size distributions. The combined techniques allow elucidation of complex aggregation kinetics and are used to reveal multiple stages of amyloid fibril formation.

International audience; OBJECTIVE: The somatotropic axis (growth hormone [GH] and insulinlike growth factor I [IGFI]) play a role in the cognitive deficits seen with aging, GH deficiency, and neurodegenerative disorders such as Alzheimer disease. We recently reported elevations in basal plasma GH and IGFI levels in patients with Huntington disease (HD). Here, our objective was to determine whether somatotropic axis abnormalities predicted cognitive dysfunction in HD. METHODS: In this prospective cohort study of 109 patients with genetically documented HD, aged 21 to 85 years, we determined fasting blood levels of total IGFI, GH, and insulinlike factor binding protein 3 at baseline, and we used the cognitive Unified Huntington's Disease Rating Scale to assess cognitive impairment at baseline and for up to 5 years subsequently. Associations were evaluated using mixed linear model analysis. RESULTS: Higher plasma IGFI concentrations were associated with greater cognitive decline (beta Stroop Words, -6.01, p = 0.003; beta Stroop Color, -4.41, p = 0.01; beta Stroop Color/Words, -3.86, p = 0.02; beta Symbol Digit Modalities, -3.69, p = 0.03; and beta verbal fluency, -5.01, p = 0.03). Higher free IGFI concentrations and higher GH concentrations in men also predicted greater cognitive decline. CONCLUSIONS: Our findings in patients with HD suggest that a high IGFI level at baseline may be associated with greater subsequent declines in executive function and attention.

International audience; Huntington disease (HD) is caused by an expansion of CAG repeat in the Huntingtin gene. Patients demonstrate a triad of motor, cognitive and psychiatric symptoms. A transgenic rat model (tgHD rats) carrying 51 CAG repeats demonstrate progressive striatal degeneration and polyglutamine aggregates in limbic structures. In this model, emotional function has only been investigated through anxiety studies. Our aim was to extend knowledge on emotional and motivational function in symptomatic tgHD rats. We subjected tgHD and wild-type rats to behavioral protocols testing motor, emotional, and motivational abilities. From 11 to 15 months of age, animals were tested in emotional perception of sucrose using taste reactivity, acquisition, extinction, and re-acquisition of discriminative Pavlovian fear conditioning as well as reactivity to changes in reinforcement values in a runway Pavlovian approach task. Motor tests detected the symptomatic status of tgHD animals from 11 months of age. In comparison to wild types, transgenic animals exhibited emotional blunting of hedonic perception for intermediate sucrose concentration. Moreover, we found emotional alterations with better learning and re-acquisition of discriminative fear conditioning due to a higher level of conditioned fear to aversive stimuli, and hyper-reactivity to a negative hedonic shift in reinforcement value interpreted in term of greater frustration. Neuropathological assessment in the same animals showed a selective shrinkage of the central nucleus of the amygdala. Our results showing emotional blunting and hypersensitivity to negative emotional situations in symptomatic tgHD animals extend the face validity of this model regarding neuropsychiatric symptoms as seen in manifest HD patients, and suggest that some of these symptoms may be related to amygdala dysfunction.

Background Huntingtin (htt) is a multi-domain protein of 350 kDa that is mutated in Huntington's disease (HD) but whose function is yet to be fully understood. This absence of information is due in part to the difficulty of manipulating large DNA fragments by using conventional molecular cloning techniques. Consequently, few studies have addressed the cellular function(s) of full-length htt and its dysfunction(s) associated with the disease. Results We describe a flexible synthetic vector encoding full-length htt called pARIS-htt (A daptable, R NAi I nsensitive & S ynthetic). It includes synthetic cDNA coding for full-length human htt modified so that: 1) it is improved for codon usage, 2) it is insensitive to four different siRNAs allowing gene replacement studies, 3) it contains unique restriction sites (URSs) dispersed throughout the entire sequence without modifying the translated amino acid sequence, 4) it contains multiple cloning sites at the N and C-ter ends and 5) it is Gateway compatible. These modifications facilitate mutagenesis, tagging and cloning into diverse expression plasmids. Htt regulates dynein/dynactin-dependent trafficking of vesicles, such as brain-derived neurotrophic factor (BDNF)-containing vesicles, and of organelles, including reforming and maintenance of the Golgi near the cell centre. We used tests of these trafficking functions to validate various pARIS-htt constructs. We demonstrated, after silencing of endogenous htt, that full-length htt expressed from pARIS-htt rescues Golgi apparatus reformation following reversible microtubule disruption. A mutant form of htt that contains a 100Q expansion and a htt form devoid of either HAP1 or dynein interaction domains are both unable to rescue loss of endogenous htt. These mutants have also an impaired capacity to promote BDNF vesicular trafficking in neuronal cells. Conclusion We report the validation of a synthetic gene encoding full-length htt protein that will facilitate analyses of its structure/function. This may help provide relevant information about the cellular dysfunctions operating during the disease. As proof of principle, we show that either polyQ expansion or deletion of key interacting domains within full-length htt protein impairs its function in transport indicating that HD mutation induces defects on intrinsic properties of the protein and further demonstrating the importance of studying htt in its full-length context.

The serotonin (5-hydroxytryptamine; 5-HT)2C receptor is a G protein-coupled receptor (GPCR) exclusively expressed in CNS that has been implicated in numerous brain disorders, including anxio-depressive states. Like many GPCRs, 5-HT2C receptors physically interact with a variety of intracellular proteins in addition to G proteins. Here, we show that calmodulin (CaM) binds to a prototypic Ca2+-dependent “1-10” CaM-binding motif located in the proximal region of the 5-HT2C receptor C-terminus upon receptor activation by 5-HT. Mutation of this motif inhibited both β-arrestin recruitment by 5-HT2C receptor and receptor-operated extracellular signal-regulated kinase (ERK) 1,2 signaling in human embryonic kidney-293 cells, which was independent of G proteins and dependent on β-arrestins. A similar inhibition was observed in cells expressing a dominant-negative CaM or depleted of CaM by RNA interference. Expression of the CaM mutant also prevented receptor-mediated ERK1,2 phosphorylation in cultured cortical neurons and choroid plexus epithelial cells that endogenously express 5-HT2C receptors. Collectively, these findings demonstrate that physical interaction of CaM with recombinant and native 5-HT2C receptors is critical for G protein-independent, arrestin-dependent receptor signaling. This signaling pathway might be involved in neurogenesis induced by chronic treatment with 5-HT2C receptor agonists and their antidepressant-like activity.

International audience; Spinocerebellar ataxia 17 (SCA17) or Huntington's disease-like-4 is a neurodegenerative disease caused by the expansion above 44 units of a CAG/CAA repeat in the coding region of the TATA box binding protein (TBP) gene leading to an abnormal expansion of a polyglutamine stretch in the corresponding protein. Alleles with 43 and 44 repeats have been identified in sporadic cases and their pathogenicity remains uncertain. Furthermore, incomplete penetrance of pathological alleles with up to 49 repeats has been suggested. The imperfect nature of the repeat makes intergenerational instability extremely rare and de novo mutations are most likely the result of partial duplications. This is one of the rarer forms of autosomal dominant cerebellar ataxia but the associated phenotype is often severe, involving various systems (cerebral cortex, striatum, and cerebellum), with extremely variable age at onset (range: 3-75 years) and clinical presentation. This gene is thought to account for a small proportion of patients with a Huntington's disease-like phenotype and cerebellar signs. Parkinson's disease-like, Creutzfeldt-Jakob disease-like and Alzheimer disease-like phenotypes have also been described with small SCA17 expansions. The abnormal protein is expressed at the same level as its normal counterpart and forms neuronal intranuclear inclusions containing other proteins involved in protein folding or degradation. The increase in the size of the glutamine stretch enhances transcription in vitro, probably leading to transcription deregulation. Interestingly, the TBP protein mutated in SCA17 is recruited in the inclusions of other polyglutaminopathies, suggesting its involvement in the transcription down-regulation observed in these diseases.

Huntington's disease is a neurodegenerative disease caused by a polyglutamine (polyQ) expansion in Huntingtin, which provokes aggregation of a proteolytic amino-terminal fragment of the affected protein encompassing the polyQ expansion. Accumulation of mutant Huntingtin somehow triggers cellular dysfunction and leads to a progressive degeneration of striatal neurons. Despite considerable efforts, the function of Huntingtin as well as the precise molecular mechanisms by which the expanded polyQ elicits cellular dysfunction remain unclear. In addition, no treatment is available to prevent, cure, or even slow down the progression of this devastating disorder. Antibodies are valuable tools to understand protein function and disease mechanisms. Here, we have identified the epitope recognized by the mAb 2B4, a broadly used antibody generated against the amino-terminal region of Huntingtin, which detects both aggregated and soluble Huntingtin. The 2B4 antibody specifically recognizes amino acids 50-64 of human Huntingtin but not the murine homologous region. Furthermore, the 2B4 epitope resides within the proline-rich region of Huntingtin, which is critical for polyQ aggregation and toxicity. These properties suggest that the 2B4 antibody might be useful in antibody-based therapeutic strategies.

International audience

International audience; Huntington's disease (HD), an inherited neurodegenerative disorder, results from an abnormal polyglutamine extension in the N-terminal region of the huntingtin protein. This mutation leads to protein aggregation and neurotoxicity. Despite its widespread expression in the brain and body, mutated huntingtin causes selective degeneration of striatal projection neurons. In the present study, we investigate the role of dopamine (DA) in this preferential vulnerability. Using primary cultures of striatal neurons transiently expressing GFP-tagged-exon 1 of mutated huntingtin, we show that low doses of DA (100 microM) act synergistically with mutated huntingtin to activate the proapoptotic transcription factor c-Jun. Surprisingly, DA also increases aggregate formation of mutated huntingtin in all cellular compartments, including neurites, soma, and nuclei. DA-dependent potentiation of c-Jun activation was reversed by ascorbate, a reactive oxygen species (ROS) scavenger, and SP-600125, a selective inhibitor of the c-Jun N-terminal kinase (JNK) pathway. By contrast, DA effects on aggregate formation were reversed by a selective D2 receptor antagonist and reproduced by a D2 agonist. Similarly, striatal neurons from D2 knockout mice showed no effect of DA on aggregate formation. Blocking ROS production, JNK activation, or D2 receptor stimulation significantly reversed DA aggravation of mutated huntingtin-induced striatal death. The combined treatment with the ROS scavenger and D2 antagonist totally reversed DA's effects on mutated huntingtin-induced striatal death. Thus, the present results provide insights into the cellular mechanisms that govern striatal vulnerability in HD and strongly support a dual role of JNK activation and D2 receptor signaling in this process.

International audience; Huntington's Disease (HD) is a late-onset, progressively degenerative brain disorder characterized by cell loss in the striatum and cortex. HD is caused by a polyglutamine (polyQ) expansion in the protein huntingtin (Htt). The mutant Htt is a substrate for caspases -2, -3 and -6. The cleavage of mutant Htt by caspase-2 has been suggested to underlie the selective neuronal death in HD. Once the mutant Htt is cleaved, a sticky and toxic fragment with the potential to form aggregates is released. The role of aggregation in the progression of HD has been extensively studied, yielding a plethora of ambivalent results. It has been shown that these are the diffuse, monomeric and oligomeric, forms of the mutant Htt fragment rather than the aggregates that are the major source of toxicity to the cells. We present here a mathematical model for aggregation in HD and discuss how it can relate to the selective neuronal death and the dependence of the disease onset on polyQ length. We describe the dynamical behavior of caspase-2, the release of monomeric forms of the mutant Htt fragment and the aggregation of these fragments through intermediate steps. Our model predicts that the concentration of toxic, intermediate oligomeric structures does not increase with increased caspase activity. We therefore suggest that the intermediate oligomeric forms of toxic Htt fragment do not account for selective and polyQ dependent neuronal death.

International audience; Huntington's disease (HD) is caused by abnormal polyglutamine (polyQ) expansion in the protein huntingtin. We have previously demonstrated the importance of the insulin-like growth factor I (IGF-1)/Akt pathway in HD. Indeed, upon IGF-1 activation, Akt phosphorylates polyQ-huntingtin at serine 421 and abrogates its toxicity. In addition, we have demonstrated that Akt is altered in the brain of HD patients. Here, we investigate the role of the serum- and glucocorticoid-induced kinase (SGK) in HD. We show that SGK phosphorylates huntingtin at serine 421 and that phosphorylation can protect striatal neurons against polyQ-huntingtin-induced toxicity. We find that SGK levels are increased in the brain of HD patients. Using a cellular model of HD, we demonstrate that the SGK dysregulation induced by polyQ-huntingtin occurs via the p38/MAPK pathway. Collectively, our results strongly suggest the involvement of SGK in HD and further imply that IGF-1 downstream signalling is a key transduction pathway that regulates the toxicity of huntingtin.

International audience; Huntington's disease (HD) is generally considered a prototypic motor disorder, but cognitive deficits are also prominent features of the disease. Systemic administration of the mitochondrial toxin 3-nitropropionic acid (3NP) has been proposed to be a phenotypic model of HD in rats and nonhuman primates. In this study, we investigated the effect of 5 days continuous subcutaneous infusion of 3NP on motor and cognitive abilities in Lewis rats. Intoxicated animals developed a motor syndrome consisting of bradykinesia as well as gait abnormalities and dystonic hindlimbs. Results from learning tasks showed that these rats: (1) did not exhibit learning deficits per se in our discrimination task but showed impairments in inhibiting behavioral responses when a transfer of learning (to new stimuli) or a transfer of response (new position of the lever) was required; (2) showed a marked tendency to persevere in choosing the compartment they previously visited in a T maze, thus leading to a clear retardation in learning a reinforced alternation task; and (3) did not show any memory deficit when a delay was introduced. Six months later, histological analyses showed severe neurodegeneration within the lateral striatum accompanied by apparent cell loss in the ventral pallidum and entopedoncular nucleus. We suggest that the 3NP rat model of basal ganglia neurodegeneration may provide a useful model for studying certain fundamental aspects of the physiopathology of HD and for evaluating the functional efficacy of new therapeutic strategies.

International audience; Abnormal CAG expansions in the IT-15 gene are associated with Huntington disease (HD). In the diagnostic setting it is necessary to define the limits of the CAG size ranges on normal and HD-associated chromosomes. Most large analyses that defined the limits of the normal and pathological size ranges employed PCR assays, which included the CAG repeats and a CCG repeat tract that was thought to be invariant. Many of these experiments found an overlap between the normal and disease size ranges. Subsequent findings that the CCG repeats vary by 8 trinucleotide lengths suggested that the limits of the normal and disease size ranges should be reevaluated with assays that exclude the CCG polymorphism. Since patients with between 30 and 40 repeats are rare, a consortium was assembled to collect such individuals. All 178 samples were reanalyzed in Cambridge by using assays specific for the CAG repeats. We have optimized methods for reliable sizing of CAG repeats and show cases that demonstrate the dangers of using PCR assays that include both the CAG and CCG polymorphisms. Seven HD patients had 36 repeats, which confirms that this allele is associated with disease. Individuals without apparent symptoms or signs of HD were found at 36 repeats (aged 74, 78, 79, and 87 years), 37 repeats (aged 69 years), 38 repeats (aged 69 and 90 years), and 39 repeats (aged 67, 90, and 95 years). The detailed case histories of an exceptional case from this series will be presented: a 95-year-old man with 39 repeats who did not have classical features of HD. The apparently healthy survival into old age of some individuals with 36-39 repeats suggests that the HD mutation may not always be fully penetrant.

International audience; Autoradiographic techniques were used to study the distribution of histamine H2-receptors as labeled with [125I]iodoaminopotentidine in the brains of patients affected by human neurodegenerative pathologies, as compared with control cases. The highest levels of histamine H2 binding sites in control cases were found in the caudate, putamen, and accumbens nuclei. In Huntington's chorea, the levels of histamine H2-receptor binding sites were found to be markedly decreased in virtually all regions examined, particularly in the putamen and globus pallidus lateralis. The loss of binding sites was related to the grade of the disease. Losses were more marked in grade III disease cases. The possible influence of neuroleptic treatment, commonly used in Huntington's patients, was studied by including samples from clinically treated schizophrenic patients. A moderate increase in the densities of [125I]iodoaminopotentidine was found in the globus pallidus of these patients. In Parkinson's disease, the levels of histamine H2-receptor binding sites were found not to be significantly different from those of control cases. These results were comparable with those obtained from unilaterally neurotoxin-lesioned guinea pigs. Similar losses of binding sites were observed in the quinolinic acid lesioned striatal intrinsic neurons in the guinea pig, whereas lesioning dopaminergic cell bodies in the substantia nigra with 6-hydroxydopamine did not produce any significant change. These results strongly suggest that histamine H2-receptors are expressed by striatal neurons, which degenerate in Huntington's chorea, but not by nigral dopaminergic neurons and may play a role in the regulation of the intact striato-nigral pathway.

International audience

International audience; The presymptomatic diagnosis of Huntington chorea (HC) by genic amplification (PCR: polymerase chain reaction) of a DNA G8 sequence containing a polymorphic HindIII site was tested in a particular HC genealogy. The advantage of this method are discussed.