Huntington's Disease Progression Research Articles

Cognitive and Motor Norms for Huntington's Disease.

The progression of Huntington's disease (HD) for gene-expanded carriers is well-studied. Natural aging effects, however, are not often considered in the evaluation of HD progression. To examine the effects of natural aging for healthy controls and to develop normative curves by age, sex, and education from the distribution of observed scores for the Symbol Digit Modalities Test, Stroop Word Reading Test, Stroop Color Naming Test, Stroop Interference Test, Total Motor Score, and Total Functional Capacity (TFC) from the Unified Huntington's Disease Rating Scale (UHDRS) along with a composite score. After combining longitudinal REGISTRY and Enroll-HD data, we used quantile regression and natural cubic splines for age to fit models for healthy controls (N=3,394; N observations=8,619). Normative curves were estimated for the 0.05, 0.25, 0.50, 0.75, and 0.95 quantiles. Two types of reference curves were considered: unconditional curves were dependent on age alone, whereas conditional curves were dependent on age and other covariates, namely sex and education. Conditioning on education was necessary for the Symbol Digit, Stroop Word, Stroop Color, Stroop Interference, and composite UHDRS. Unconditional curves were sufficient for the Total Motor Score. TFC was unique in that the curve was constant over age with its intercept at the maximum score (TFC=13). For all measures, sex effects were minimal, so conditioning on sex was unwarranted. Extreme quantile estimates for each measure can be considered as boundaries for natural aging and scores falling beyond these thresholds are likely the result of disease progression. Normative curves and tables are developed and can serve as references for clinical characterization in HD.

Impact of differential and time-dependent autophagy activation on therapeutic efficacy in a model of Huntington disease

ABSTRACT Activation of macroautophagy/autophagy, a key mechanism involved in the degradation and removal of aggregated proteins, can successfully reverse Huntington disease phenotypes in various model systems. How neuronal autophagy impairments need to be considered in Huntington disease progression to achieve a therapeutic effect is currently not known. In this study, we used a mouse model of HTT (huntingtin) protein aggregation to investigate how different methods and timing of autophagy activation influence the efficacy of autophagy-activating treatment in vivo. We found that overexpression of human TFEB, a master regulator of autophagy, did not decrease mutant HTT aggregation. On the other hand, Becn1 overexpression, an autophagic regulator that plays a key role in autophagosome formation, partially cleared mutant HTT aggregates and restored neuronal pathology, but only when administered early in the disease progression. When Becn1 was administered at a later stage, when prominent mutant HTT accumulation and autophagy impairments have occurred, Becn1 overexpression did not rescue the mutant HTT-associated phenotypes. Together, these results demonstrate that the targets used to activate autophagy, as well as the timing of autophagy activation, are crucial for achieving efficient therapeutic effects.Abbreviations: AAV: adeno-associated viral vectors; ACTB: actin beta; BECN1: beclin 1, autophagy related; DAPI: 4ʹ,6-diamidino-2-phenylindole; GO: gene ontology; HD: Huntington disease; HTT: huntingtin; ICQ: Li’s intensity correlation quotient; IHC: immunohistochemistry; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mHTT: mutant huntingtin; PCA: principal component analysis; PPP1R1B/DARPP-32: protein phosphatase 1 regulatory inhibitor subunit 1B; SQSTM1: sequestosome 1; TFEB: transcription factor EB; WB: western blot; WT: wild-type.

Morphometric in vivo evidence of thalamic atrophy correlated with cognitive and motor dysfunction in Huntington's disease: The IMAGE-HD study

In Huntington's disease (HD), neurodegeneration causes progressive atrophy to the striatum, cortical areas, and white matter tracts - components of corticostriatal circuitry. Such processes may affect the thalamus, a key circuit node. We investigated whether differences in dorsal thalamic morphology were detectable in HD, and whether thalamic atrophy was associated with neurocognitive, neuropsychiatric and motor dysfunction.Magnetic resonance imaging scans and clinical outcome measures were obtained from 34 presymptomatic HD (pre-HD), 29 early symptomatic HD (symp-HD), and 26 healthy control individuals who participated in the IMAGE-HD study. Manual region of interest (ROI) segmentation was conducted to measure dorsal thalamic volume, and thalamic ROI underwent shape analysis using the spherical harmonic point distribution method.The symp-HD group had significant thalamic volumetric reduction and global shape deflation, indicative of atrophy, compared to pre-HD and control groups. Thalamic atrophy significantly predicted neurocognitive and motor dysfunction within the symp-HD group only.Thalamic morphology differentiates symp-HD from pre-HD and healthy individuals. Thalamic changes may be one of the structural bases (endomorphotypes), of the endophenotypic neurocognitive and motor manifestations of disease. Future research should continue to investigate the thalamus as a potential in vivo biomarker of disease progression in HD.

Estimating disease onset from change points of markers measured with error.

Huntington disease is an autosomal dominant, neurodegenerative disease without clearly identified biomarkers for when motor-onset occurs. Current standards to determine motor-onset rely on a clinician's subjective judgment that a patient's extrapyramidal signs are unequivocally associated with Huntington disease. This subjectivity can lead to error which could be overcome using an objective, data-driven metric that determines motor-onset. Recent studies of motor-sign decline-the longitudinal degeneration of motor-ability in patients-have revealed that motor-onset is closely related to an inflection point in its longitudinal trajectory. We propose a nonlinear location-shift marker model that captures this motor-sign decline and assesses how its inflection point is linked to other markers of Huntington disease progression. We propose two estimating procedures to estimate this model and its inflection point: one is a parametric method using nonlinear mixed effects model and the other one is a multi-stage nonparametric approach, which we developed. In an empirical study, the parametric approach was sensitive to correct specification of the mean structure of the longitudinal data. In contrast, our multi-stage nonparametric procedure consistently produced unbiased estimates regardless of the true mean structure. Applying our multi-stage nonparametric estimator to Neurobiological Predictors of Huntington Disease, a large observational study of Huntington disease, leads to earlier prediction of motor-onset compared to the clinician's subjective judgment.

PET Molecular Imaging of Phosphodiesterase 10A: An Early Biomarker of Huntington's Disease Progression.

Changes in phosphodiesterase 10A enzyme levels may be a suitable biomarker of disease progression in Huntington's disease. To evaluate phosphodiesterase 10A PET imaging as a biomarker of HD progression using the radioligand, [18 F]MNI-659. The cross-sectional study (NCT02061722) included 45 Huntington's disease gene-expansion carriers stratified into four disease stages (early and late premanifest and Huntington's disease stages 1 and 2) and 45 age- and sex-matched healthy controls. The primary analysis compared striatal and pallidal phosphodiesterase 10A availability between Huntington's disease gene-expansion carriers and healthy controls as assessed by [18 F]MNI-659 binding. We assessed changes in phosphodiesterase 10A expression using several PET methodologies and compared with previously proposed measures of Huntington's disease progression (PET imaging of D2/3 receptors and anatomical volume loss on MRI). The longitudinal follow-up study (NCT02956148) continued evaluation of phosphodiesterase 10A availability in 35 Huntington's disease gene-expansion carriers at a mean of 18 months from baseline of the cross-sectional study. Primary analyses revealed that phosphodiesterase 10A availability in caudate, putamen, and globus pallidus was significantly lower in Huntington's disease gene-expansion carriers versus healthy controls across all stages. Striatal and pallidal phosphodiesterase 10A availability progressively declined in the premanifest stages and appeared to plateau between stages 1 and 2. The percentage decline of phosphodiesterase 10A availability measured cross-sectionally between Huntington's disease gene-expansion carriers and healthy controls was greater than that demonstrated by D2/3 receptor availability or volumetric changes. Annualized rates of phosphodiesterase 10A change showed a statistically significant decline between the cross-sectional study and follow-up. [18 F]MNI-659 PET imaging is a biologically plausible biomarker of Huntington's disease progression that is more sensitive than the dopamine-receptor and volumetric methods currently used. © 2020 International Parkinson and Movement Disorder Society.

The effects of dual-task cognitive interference on gait and turning in Huntington’s disease

Huntington’s disease (HD) is characterized by motor, cognitive, and psychiatric dysfunction. HD progression causes loss of automaticity, such that previously automatic tasks require greater attentional resources. Dual-task (DT) paradigms and fast-paced gait may stress the locomotor system, revealing deficits not seen under single-task (ST). However, the impact of gait “stress tests” on HD individuals needs further investigation. Therefore, the aims of this study were to investigate whether: 1) fast-paced and dual-task walking uncover deficits in gait and turning not seen under single-task, 2) cognitive and gait outcomes relate to fall incidence, and 3) gait deficits measured with wearable inertial sensors correlate with motor symptom severity in HD as measured by the Unified Huntington’s disease Rating Scale-total motor score (UHDRS-TMS). Seventeen HD (55 ± 9.7 years) and 17 age-matched controls (56.5 ± 9.3 years) underwent quantitative gait testing via a 25m, two-minute walk test with APDMTM inertial sensors. Gait was assessed under a 1) ST, self-selected pace, 2) fast-as-possible (FAP) pace, and 3) verbal fluency DT. The UHDRS-TMS and a cognitive test battery were administered, and a retrospective fall history was obtained. During ST, DT, and FAP conditions, HD participants demonstrated slower gait, shorter stride length, and greater lateral step and stride length variability compared to controls (p<0.00001 to 0.034). Significant dual-task costs (DTC) were observed for turns; HD participants took more time (p = 0.013) and steps (p = 0.028) to complete a turn under DT compared to controls. Higher UHDRS-TMS correlated with greater stride length variability, less double-support, and more swing-phase time under all conditions. Decreased processing speed was associated with increased gait variability under ST and FAP conditions. Unexpectedly, participant’s self-reported falls did not correlate with any gait or turn parameters. HD participants demonstrated significantly greater DTC for turning, which is less automatic than straight walking, requiring coordination of body segments, anticipatory control, and cortical regulation. Turn complexity likely makes it more susceptible to cognitive interference in HD.

Bioinformatic analysis of a microRNA regulatory network in Huntington's disease.

Huntington's disease is an autosomal dominant hereditary neurodegenerative disease characterized by progressive dystonia, chorea and cognitive or psychiatric disturbances. The leading cause is the Huntington gene mutation on the patient's chromosome 4 that produces a mutated protein. Recently, attention has focused on the relationship between microRNAs and Huntington's disease's pathogenesis. In Huntington's disease, microRNAs can interact with various transcriptionfactors; dysregulated microRNAs may be associated with the Cytosine deoxynucleotide-Adenine ribonucleotides-Guanine ribonucleotide length and Huntington's disease's progression and severity. This study explores the role of microRNAs in the pathogenesis of Huntington's disease through bioinformatics analysis. By analyzing data from the Gene Expression Omnibus database, we identified a total of 9 differentially expressed microRNA. Subsequently, target genes and long non-coding RNAs were predicted, and a comprehensive regulatory network centered on microRNA was constructed. The microRNA integrated regulatory network, Homo sapiens (hsa)-miR-144-3p, interacted with the largest number of long non-coding RNAs, including X-inactive specific transcriptand taurine upregulated gene 1. The miRNAs, hsa-miR-10b-5p and hsa-miR-196a-5p, regulated most of the target genes, including class I homeobox and brain-derived neurotrophic factorgenes. Additionally, 59 Gene Ontology terms and eight enrichment pathways were identified by analyzing the target genes of hsa-miR-196a-5p and hsa-microRNA-10b-5p. In conclusion, hsa-miR-10b-5p and hsa-miR-196a-5p were significantly and differentially expressed in Huntington's disease, the long non-coding RNAs X-inactive specific transcript, taurine upregulated gene 1, and target genes such as homeobox or brain-derived neurotrophic factor may play critical roles in the pathogenesis of Huntington's disease.

Role of Phosphorylated Tau and Glucose Synthase Kinase 3 Beta in Huntington's Disease Progression.

The purpose of our article is to critically assess the role of phosphorylated tau in Huntington's disease (HD) progression and pathogenesis. HD is a fatal and pure genetic disease, characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment, and emotional disturbances. HD is caused by expanded polyglutamine (polyQ or CAG) repeats within the exon 1 of the HD gene. HD has an autosomal dominant pattern of inheritance with genetic anticipation. Although the HD gene was discovered 26 years ago, there is no complete understanding of how mutant huntingtin (mHTT) selectively targets medium spiny projection neurons in the basal ganglia of the brain in patients with HD. Several years of intense research revealed that multiple cellular changes are involved in disease process, including transcriptional dysregulation, mitochondrial abnormalities and impaired bioenergetics, defective axonal transport, calcium dyshomeostasis, synaptic damage and caspase, and NMDAR activations. Recent research also revealed that phosphorylated tau and defective GSK-3β signaling are strongly linked to progression of the disease. This article summarizes the recent developments of cellular and pathological changes in disease progression of HD. This article also highlights recent developments in phosphorylated tau and defective GSK-3β signaling and the involvement of calcineurin in HD progression and pathogenesis.

Targeted Depletion of Primary Cilia in Dopaminoceptive Neurons in a Preclinical Mouse Model of Huntington's Disease.

Multiple pathomechanisms triggered by mutant Huntingtin (mHTT) underlie progressive degeneration of dopaminoceptive striatal neurons in Huntington’s disease (HD). The primary cilium is a membrane compartment that functions as a hub for various pathways that are dysregulated in HD, for example, dopamine (DA) receptor transmission and the mechanistic target of rapamycin (mTOR) pathway. The roles of primary cilia (PC) for the maintenance of striatal neurons and in HD progression remain unknown. Here, we investigated PC defects in vulnerable striatal neurons in a progressive model of HD, the mHTT-expressing knock-in zQ175 mice. We found that PC length is affected in striatal but not in cortical neurons, in association with the accumulation of mHTT. To explore the role of PC, we generated conditional mutant mice lacking IFT88, a component of the anterograde intraflagellar transport-B complex lacking PC in dopaminoceptive neurons. This mutation preserved the expression of the dopamine 1 receptor (D1R), and the survival of striatal neurons, but resulted in a mild increase of DA metabolites in the striatum, suggesting an imbalance of ciliary DA receptor transmission. Conditional loss of PC in zQ175 mice did not trigger astrogliosis, however, mTOR signaling was more active and resulted in a more pronounced accumulation of nuclear inclusions containing mHTT. Further studies will be required of aged mice to determine the role of aberrant ciliary function in more advanced stages of HD.

CD200 is up-regulated in R6/1 transgenic mouse model of Huntington's disease.

In Huntington’s disease (HD), striatal medium spiny neurons (MSNs) are particularly sensitive to the presence of a CAG repeat in the huntingtin (HTT) gene. However, there are many evidences that cells from the peripheral immune system and central nervous system (CNS) immune cells, namely microglia, play an important role in the etiology and the progression of HD. However, it remains unclear whether MSNs neurodegeneration is mediated by a non-cell autonomous mechanism. The homeostasis in the healthy CNS is maintained by several mechanisms of interaction between all brain cells. Neurons can control microglia activation through several inhibitory mechanisms, such as the CD200–CD200R1 interaction. Due to the complete lack of knowledge about the CD200–CD200R1 system in HD, we determined the temporal patterns of CD200 and CD200R1 expression in the neocortex, hippocampus and striatum in the HD mouse models R6/1 and HdhQ111/7 from pre-symptomatic to manifest stages. In order to explore any alteration in the peripheral immune system, we also studied the levels of expression of CD200 and CD200R1 in whole blood. Although CD200R1 expression was not altered, we observed and increase in CD200 gene expression and protein levels in the brain parenchyma of all the regions we examined, along with HD pathogenesis in R6/1 mice. Interestingly, the expression of CD200 mRNA was also up-regulated in blood following a similar temporal pattern. These results suggest that canonical neuronal–microglial communication through CD200–CD200R1 interaction is not compromised, and CD200 up-regulation in R6/1 brain parenchyma could represent a neurotrophic signal to sustain or extend neuronal function in the latest stages of HD as pro-survival mechanism.

Early Intrathecal T Helper 17.1 Cell Activity in Huntington Disease.

Huntington disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. No disease-modifying therapy exists for the treatment of patients with HD. The purpose of this study was therefore to investigate early disease mechanisms that potentially could be used as a target therapeutically. Lymphocyte activity in cerebrospinal fluid (CSF) from 4 cohorts of HTT gene expansion carriers (n = 121 in total) and controls was analyzed by techniques based on flow cytometry and enzyme-linked immunosorbent assays. The data of this study provide evidence of immune abnormalities before motor onset of disease. In CSF of HTT gene expansion carriers, we found increased levels of proinflammatory cytokines, including IL-17, and increased consumption of the lymphocyte growth factor IL-7 before motor onset of HD. In concordance, we observed an increased prevalence of IL-17-producing Th17.1 cells in the CSF of HTT gene expansion carriers, predominantly in pre-motor manifest individuals. The frequency of intrathecal Th17.1 cells correlated negatively with progression of HD and the level of neurodegeneration, suggesting a role of Th17.1 cells in the early disease stage. We also observed a skewing in the balance between proinflammatory and regulatory T cells potentially favoring a proinflammatory intrathecal environment in HTT gene expansion carriers. These data suggest that Th17.1 cells are implicated in the earliest pathogenic phases of HD and suggest that treatment to dampen T -cell-driven inflammation before motor onset might be of benefit in HTT gene expansion carriers. ANN NEUROL 2020;87:246-255.

Impaired face-like object recognition in premanifest Huntington's disease

Progressive striatal atrophy has long been considered the pathological hallmark of Huntington's disease (HD), but is it now recognized that malfunction and degeneration of posterior-cortical territories are also prominent characteristics of the disease. The limited knowledge about the functional impact of these posterior-cortical changes could be partially attributed to the lack of sensitive measures to capture them. We hypothesized that early malfunction of specific territories of the ventral visual pathway in premanifest HD would lead to difficulties in the recognition of complex stimuli and to differences in their neurophysiological correlates. To test this idea, we used an object, face and face-like object recognition task to be conducted during an electroencephalographic recording. Compared to healthy-matched controls, premanifest participants showed a significantly increased number of recognition errors in the face-like object condition. Moreover, premanifest participants showed a dramatic decrease in the N170 component elicited for the face-like objects. This N170 decrease was significantly associated with the number of recognition errors and with severity of apathy and global cognitive performance. The lack of differences in other clinical and cognitive measures supports a selective deficit in recognition of face-like objects and their neurophysiological correlates in premanifest HD. These deficits occurred in participants up to 15 years before the estimated time to disease onset and correlated strongly with cognitive and behavioral measures known to be sensitive to HD progression. This finding highlights the existence of selective visuoperceptive deficits years before motor-based onset of HD and emphasizes the need to develop sensitive measures to capture early visual system changes in this population. Assessing the integrity of the visual cortex and its related functions in HD could help to identify early markers of disease progression.

The Role of Microglia and Astrocytes in Huntington’s Disease

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease. HD patients present with movement disorders, behavioral and psychiatric symptoms and cognitive decline. This review summarizes the contribution of microglia and astrocytes to HD pathophysiology. Neuroinflammation in the HD brain is characterized by a reactive morphology in these glial cells. Microglia and astrocytes are critical in regulating neuronal activity and maintaining an optimal milieu for neuronal function. Previous studies provide evidence that activated microglia and reactive astrocytes contribute to HD pathology through transcriptional activation of pro-inflammatory genes to perpetuate a chronic inflammatory state. Reactive astrocytes also display functional changes in glutamate and ion homeostasis and energy metabolism. Astrocytic and microglial changes may further contribute to the neuronal death observed with the progression of HD. Importantly, the degree to which these neuroinflammatory changes are detrimental to neurons and contribute to the progression of HD pathology is not well understood. Furthermore, recent observations provide compelling evidence that activated microglia and astrocytes exert a variety of beneficial functions that are essential for limiting tissue damage and preserving neuronal function in the HD brain. Therefore, a better understanding of the neuroinflammatory environment in the brain in HD may lead to the development of targeted and innovative therapeutic opportunities.

Glycation in Huntington's Disease: A Possible Modifier and Target for Intervention.

Glycation is the non-enzymatic reaction between reactive dicarbonyls and amino groups, and gives rise to a variety of different reaction products known as advanced glycation end products (AGEs). Accumulation of AGEs on proteins is inevitable, and is associated with the aging process. Importantly, glycation is highly relevant in diabetic patients that experience periods of hyperglycemia. AGEs also play an important role in neurodegenerative diseases including Alzheimer’s (AD) and Parkinson’s disease (PD). Huntington’s disease (HD) is a hereditary neurodegenerative disease caused by an expansion of a CAG repeat in the huntingtin gene. The resulting expanded polyglutamine stretch in the huntingtin (HTT) protein induces its misfolding and aggregation, leading to neuronal dysfunction and death. HD patients exhibit chorea and psychiatric disturbances, along with abnormalities in glucose and energy homeostasis. Interestingly, an increased prevalence of diabetes mellitus has been reported in HD and in other CAG triplet repeat disorders. However, the mechanisms underlying the connection between glycation and HD progression remain unclear. In this review, we explore the possible connection between glycation and proteostasis imbalances in HD, and posit that it may contribute to disease progression, possibly by accelerating protein aggregation and deposition. Finally, we review therapeutic interventions that might be able to alleviate the negative impact of glycation in HD.

Association of CAG Repeats With Long-term Progression in Huntington Disease

In Huntington disease (HD), mutation severity is defined by the length of the CAG trinucleotide sequence, a well-known predictor of clinical onset age. The association with disease trajectory is less well characterized. Quantifiable summary measures of trajectory applicable over decades of early disease progression are lacking. An accurate model of the age-CAG association with early progression is critical to clinical trial design, informing both sample size and intervention timing. To succinctly capture the decades-long early progression of HD and its dependence on CAG repeat length. Prospective study at 4 academic HD treatment and research centers. Participants were the combined sample from the TRACK-HD and Track-On HD studies consisting of 290 gene carriers (presymptomatic to stage II), recruited from research registries at participating centers, and 153 nonbiologically related controls, generally spouses or friends. Recruitment was targeted to match a balanced, prespecified spectrum of age, CAG repeat length, and diagnostic status. In the TRACK-HD and Track-On HD studies, 13 and 5 potential participants, respectively, failed study screening. Follow-up ranged from 0 to 6 years. The study dates were January 2008 to November 2014. These analyses were performed between December 2015 and January 2019. The outcome measures were principal component summary scores of motor-cognitive function and of brain volumes. The main outcome was the association of these scores with age and CAG repeat length. We analyzed 2065 visits from 443 participants (247 female [55.8%]; mean [SD] age, 44.4 [10.3] years). Motor-cognitive measures were highly correlated and had similar CAG repeat length-dependent associations with age. A composite summary score accounted for 67.6% of their combined variance. This score was well approximated by a score combining 3 items (total motor score, Symbol Digit Modalities Test, and Stroop word reading) from the Unified Huntington's Disease Rating Scale. For either score, initial progression age and then acceleration rate were highly CAG repeat length dependent. The acceleration continues through at least stage II disease. In contrast, 3 distinct patterns emerged among brain measures (basal ganglia, gray matter, and a combination of whole-brain, ventricular, and white matter volumes). The basal ganglia pattern showed considerable change in even the youngest participants but demonstrated minimal acceleration of loss with aging. Each clinical and brain summary score was strongly associated with the onset and rate of decline in total functional capacity. Results of this study suggest that succinct summary measures of function and brain loss characterize HD progression across a wide disease span. CAG repeat length strongly predicts their decline rate. This work aids our understanding of the age and CAG repeat length-dependent association between changes in the brain and clinical manifestations of HD.

Rutin and Selenium Co-administration Reverse 3-Nitropropionic Acid-Induced Neurochemical and Molecular Impairments in a Mouse Model of Huntington's Disease.

Systemic administration of 3-nitropropionic acid (3-NPA) is commonly used to induce Huntington's disease (HD)-like symptoms in experimental animals. Here, the potential neuroprotective efficiency of rutin and selenium (RSe) co-administration on 3-NPA-induced HD-like symptoms model in mice was investigated. 3-NPA injection evoked severe alterations in redox status, as indicated via increased striatal malondialdehyde and nitric oxide levels, accompanied by a decrease in levels of antioxidant molecules including glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase. Moreover, 3-NPA potentiated inflammatory status by enhancing the production of interleukin-1β, tumor necrosis factor-α, and myeloperoxidase activity. Pro-apoptotic cascade was also recorded in the striatum as evidenced through upregulation of cleaved caspase-3 and Bax, and downregulation of Bcl-2. 3-NPA activated astrocytes as indicated by the upregulated glial fibrillary acidic protein and inhibited brain-derived neurotrophic factor. Furthermore, perturbations in cholinergic and monoaminergic systems were observed. RSe provided neuroprotective effects by preventing body weight loss, oxidative stress, neuroinflammation, and the apoptotic cascade. RSe inhibited the activation of astrocytes, increased brain-derived neurotrophic factor, and improved cholinergic and monoaminergic transmission following 3-NPA intoxication. Taken together, RSe co-administration may prevent or delay the progression of HD and its associated impairments through its antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory effects.

Differential regulation of Kidins220 isoforms in Huntington's disease.

Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by brain atrophy particularly in the striatum that produces motor impairment, and cognitive and psychiatric disturbances. Multiple pathogenic mechanisms have been proposed including dysfunctions in neurotrophic support and calpain-overactivation, among others. Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), is an essential mediator of neurotrophin signaling. In adult brain, Kidins220 presents two main isoforms that differ in their carboxy-terminal length and critical protein-protein interaction domains. These variants are generated through alternative terminal exon splicing of the conventional exon 32 (Kidins220-C32) and the recently identified exon 33 (Kidins220-C33). The lack of domains encoded by exon 32 involved in key neuronal functions, including those controlling neurotrophin pathways, pointed to Kidins220-C33 as a form detrimental for neurons. However, the functional role of Kidins220-C33 in neurodegeneration or other pathologies, including HD, has not been explored. In the present work, we discover an unexpected selective downregulation of Kidins220-C33, in the striatum of HD patients, as well as in the R6/1 HD mouse model starting at early symptomatic stages. These changes are C33-specific as Kidins220-C32 variant remains unchanged. We also find the early decrease in Kidins220-C33 levels takes place in neurons, suggesting an unanticipated neuroprotective role for this isoform. Finally, using ex vivo assays and primary neurons, we demonstrate that Kidins220-C33 is downregulated by mechanisms that depend on the activation of the protease calpain. Altogether, these results strongly suggest that calpain-mediated Kidins220-C33 proteolysis modulates onset and/or progression of HD.

Towards a comprehensive understanding of the contributions of mitochondrial dysfunction and oxidative stress in the pathogenesis and pathophysiology of Huntington's disease.

Huntington's disease (HD) is a rare autosomal dominant disorder affecting the corticostriatal area of the brain. HD is driven by elongated cytosine-adenine-guanine (CAG) repeat (36 repeats or more) on the short arm of chromosome 4p16.3 in the Huntingtin gene (HTTg) which encode the huntingtin protein (HTT). Although the polyglutamine expansion within HTT is the causative factor in the pathogenesis of HD, the underlying mechanisms that provoke this expansion and the resulting neurodegeneration and clinical symptoms are not fully understood. In this paper, the critical role played by mitochondria dysfunction and oxidative stress in HTT expansion, HD progression, and clinical symptoms are elucidated. Their interactions with the key factors in the disease, as well as treatment strategies, are discussed.

Quality Control in Huntington's Disease: a Therapeutic Target.

Huntington's disease (HD) is a fatal autosomal dominantly inherited brain disease caused by excessively expanded CAG repeats in gene which encodes huntingtin protein. These abnormally encoded huntingtin proteins and their truncated fragments result in disruption of cellular quality mechanism ultimately triggering neuronal death. Despite great efforts, a potential causative agent leading to genetic mutation in HTT, manifesting the neurons more prone to oxidative stress, cellular inflammation, energy depletion and apoptotic death, has not been established yet. Current scenario concentrates on symptomatic pathologies to improvise the disease progression and to better the survival. Most of the therapeutic developments have been converged to rescue the protein homeostasis. In HD, abnormal expansion of glutamine repeats in the protein huntingtin leads to toxic aggregation of huntingtin which in turn impairs the quality control mechanism of cells through damaging the machineries involved in removal of aggregated abnormal protein. Therapeutic approaches to improve the efficiency of aggregate clearance through quality control mechanisms involve protein folding machineries such as chaperones and protein degradation machineries such as proteasome and autophagy. Also, to reduce protein aggregation by enhancing proper folding, to degrade and eliminate the aggregates are suggested to negatively regulate the HD progression associated with the disruption of protein homeostasis. This review focuses on the collection of therapeutic strategies targeting enhancement of protein quality control activity to delay the HD pathogenesis.

EGF Treatment Improves Motor Behavior and Cortical GABAergic Function in the R6/2 Mouse Model of Huntington's Disease.

Recent evidence indicates that disruption of epidermal growth factor (EGF) signaling by mutant huntingtin (polyQ-htt) may contribute to the onset of behavioral deficits observed in Huntington's disease (HD) through a variety of mechanisms, including cerebrovascular dysfunction. Yet, whether EGF signaling modulates the development of HD pathology and the associated behavioral impairments remain unclear. To gain insight on this issue, we used the R6/2 mouse model of HD to assess the impact of chronic EGF treatment on behavior, and cerebrovascular and cortical neuronal functions. We found that bi-weekly treatment with a low dose of EGF (300µg/kg, i.p.) for 6weeks was sufficient to effectively improve motor behavior in R6/2 mice and diminish mortality, compared tovehicle-treated littermates. These beneficial effects of EGF treatment were dissociated from changes in cerebrovascular leakiness, a result that was surprising given that EGF ameliorates this deficit in other neurodegenerative diseases. Rather, the beneficial effect of EGF on R6/2 mice behavior was concomitant with a marked amelioration of cortical GABAergic function. As GABAergic transmission in cortical circuits is disrupted in HD, these novel data suggest a potential mechanistic link between deficits in EGF signaling and GABAergic dysfunction in the progression of HD.