Chaperone-assisted selective autophagy (CASA) is a crucial process aimed at maintaining proteostasis in several neurodegenerative diseases associated with protein misfolding, including polyglutamine (polyQ) diseases. Autophagy is a critical lysosome-mediated degradation pathway, particularly essential in neurons, which are highly susceptible to proteotoxic stress due to their post-mitotic nature. Selective autophagy pathways, including CASA, ensure the targeted removal of misfolded proteins and damaged organelles, thereby preserving cellular homeostasis. CASA is based on the intersection of chaperones and autophagy, where HSPB8 and BAG3 interact with HSPA and STUB1 forming a complex that identifies, ubiquitinates, and directs aberrant proteins toward autophagosomes for subsequent lysosomal degradation. In polyQ diseases, such as spinal and bul muscular atrophy (SBMA) and Huntington's disease (HD), mutant proteins accumulate, overwhelming the protein quality control systems. The CASA components are upregulated as a compensatory response, promoting toxic aggregates clearance and cellular damage mitigation. However, chronic proteotoxic stress and progressive impairment of autophagic and lysosomal pathways eventually limit CASA efficiency, contributing to disease progression. The review highlights how CASA exerts its protective activities in polyQ diseases and reports therapeutic strategies aimed at enhancing CASA activity, including pharmacological inducers and combinatorial approaches targeting autophagy and the ubiquitin-proteasome system. Overall, CASA emerges as a crucial adaptive mechanism and a promising therapeutic target in polyQ-related neurodegeneration.
Emerging evidence suggests a central and early role of mitochondrial dysfunction, including altered mitochondrial dynamics, in Huntington's disease (HD) pathogenesis. Processes such as mitochondrial fission, fusion, transport and mitophagy are vital for proper mitochondrial function and seem to be key mediators of neuronal vulnerability in HD. In this review, we summarize mechanistic insights into mitochondrial dynamics in HD, highlighting how mutant huntingtin (mHTT) impairs mitochondrial biogenesis and morphology, disrupts Drp1-dependent fission, compromises fusion, transport and organelle crosstalk with the endoplasmic reticulum, and disrupts mitochondrial quality control, ultimately leading to neuronal degeneration. Since these alterations correlate with bioenergetic deficits, calcium dysregulation and oxidative stress, we highlight how altered mitochondrial dynamics contribute to and possibly drive HD pathogenesis. Furthermore, we discuss how mitochondrial dynamics in HD can be altered based on cell type specificity, experimental model and disease stage.
IntroductionReal-world evidence of deutetrabenazine (DTBZ) treatment for Huntington disease (HD)-associated chorea is limited.MethodsThis is a non-interventional, retrospective chart review study from a Huntington's Disease Society of America clinical practice at the University of Alabama at Birmingham (UAB). Patients had a diagnosis of HD-associated chorea, DTBZ initiation (4/2017-12/2021), ≥2 visits at UAB, and ≥3 months of chorea-related care records post DTBZ initiation. The last Unified HD Rating Scale-Total Maximal Chorea (TMC) score within 3 months prior to DTBZ initiation and first after reaching the last stable dose during follow-up were analyzed.ResultsAmong 80 eligible patient charts, mean (SD) age was 52.1 (12.6) years and 45 (56.3%) were female. Fifty patients had pre- and post-DTBZ TMC scores and reached a stable dose, including 30 with no prior tetrabenazine (TBZ) or DTBZ exposure, 8 with prior TBZ exposure with a switch to DTBZ after a gap, and 9 with prior TBZ exposure with a switch to DTBZ without a gap. Mean (SD) TMC score decreased (i.e., improved) by 3.7 (4.5), 7.8 (2.8), and 2.1 (4.2), respectively. Overall, 27 (33.8%) patients had ≥1 adverse event recorded between DTBZ initiation and the first visit with a TMC score after reaching their last stable DTBZ dose or DTBZ discontinuation for those without a stable dose.DiscussionThis real-world study describes improvements in TMC scores among patients with HD-associated chorea treated with DTBZ, regardless of prior treatment. The observed safety profile supports the known safety profile of DTBZ in this population.
Huntington's disease (HD) is a fatal neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin gene (HTT). While classically considered a disease of grey matter, recent imaging data have revealed presymptomatic abnormalities in white matter (WM) tracts. Here, we report lipid changes in glycerophospholipids and sphingolipids from enriched myelin extracts of three WM tracts (internal capsule (IC), dorsomedial prefrontal cortex (dmPFC), corpus callosum (CC)) of HD and control donors. We found no difference in total lipid concentration between HD and control myelin. However, changes were observed at the lipid class level for the CC and dmPFC, with a reduction in the proportion of Hexosylceramides in HD myelin. When lipids were examined at a species level, there was a shift towards shorter glycerophospholipid fatty acid chain length in HD for all three regions, most notably in phosphatidylethanolamine species. This coincides with previous data showing a reduction in fatty acyl chain lengths in sphingolipid species in the caudate of the same donor cohort and suggests a widespread impact of HD on fatty acid metabolism in the brain.
BackgroundRecent reports indicated that 4',5,7-trihydroxyisoflavone (genistein) can improve biochemical disorders and correct behavioral disturbances in cellular and animal models of Huntington's disease (HD), acting thorough stimulation of autophagy-dependent degradation of mutant huntingtin aggregates. Effects in the mouse HD model was tested previously only after appearance of symptoms of HD.ObjectiveThe aim of this work was to assess the efficacy of genistein in preventing the appearance of symptoms in the R6/1 mouse model of HD, using both males and females.MethodsA battery of behavioral tests (Rota-rod, elevated-plus maze, Morris water maze, monitoring of movements in actometer) was used, and selected biochemical and hematological parameters were determined in control (wild-type) and R6/1 (HD) mice (males and females) treated with either orally-administered genistein at 150 mg/kg/day or water (control). The treatment was initiated at 7th week of life (while the first symptoms appear at 14-16 week in this HD model), and was continued until 30th week.ResultsAdministration of genistein resulted in extension of life span and prevention of appearance of HD symptoms in R6/1 mice. The immunological and biochemical parameters were comparable between wild-type and R6/1 mice treated with genistein, whereas the untreated HD animals revealed significant differences relative to controls.ConclusionsGenistein appeared to be effective in preventing the appearance of severe symptoms of HD in the mouse R6/1 model, indicating that this compound might be considered as a potential anti-HD drug.
Understanding the trajectory of Huntington's disease (HD) is critical for patient stratification and the development of targeted interventions. Traditionally, studies relied on age-CAG models to estimate disease onset and progression, based on the well-established relationship between CAG repeat length and age at onset. However, additional genetic, environmental, and clinical factors can cause substantial variability. Recent machine learning approaches integrate clinical, imaging, and molecular data for more precise prediction of disease progression. Following PRISMA guidelines, we systematically reviewed studies on HD onset and progression. Using Web of Science, PubMed, and IEEE Xplore, 20 studies published between 2003 and 2024 met the inclusion criteria. We analyzed the machine learning approaches and input features used, assessed methodological quality, and evaluated risk of bias using the PROBAST tool. Overall, machine learning models, particularly support vector machines and ensemble approaches, consistently outperformed traditional age-CAG models. Several studies predicted conversion from premanifest to manifest HD within 5-10 years with high accuracy (88-98%). Beyond predicting onset, machine learning models have also been used to model dis-ease progression using clinical scores assessing motor, cognitive, and functional impairment. Performance was higher in studies incorporating structural and functional MRI biomarkers, and improved further with longitudinal clinical integration, enabling pre-diction of decline years before symptoms onset. Overall, machine learning shows strong potential to improve prognostic modeling in HD, especially through multimodal and longitudinal data. However, common methodological weaknesses and bias highlight the need for larger, externally validated studies using objective biomarkers.
Huntington's disease (HD) is a rare, autosomal dominant neurodegenerative disorder caused by a pathogenic CAG expansion in the huntingtin gene, classically characterized by a triad of cognitive, psychiatric, and motor symptoms. Involuntary movements known as chorea are the most notable feature of HD. Despite the negative impact chorea can have on many aspects of day-to-day life, pharmacologic treatment remains underutilized in clinical practice. Barriers include anosognosia, a complex treatment landscape, limited evidence-based guidelines, and variable access to care. In February 2025, 11 North American HD specialists and members of the Huntington Study Group (HSG) Motor Treatment Task Force, who collectively care for ∼1500 people with HD (PwHD) convened to discuss current practices and challenges in the pharmacologic treatment of chorea. Insights were supplemented by responses to a long-form questionnaire distributed via email. Attendees and respondents described practical approaches to assessing chorea, engaging care partners, and setting goal-oriented treatment plans. This review draws on collective experience to highlight practical, real-world strategies for the evaluation and treatment of HD chorea. The two most common medication classes used to suppress chorea are vesicular monoamine transporter 2 (VMAT2) inhibitors and antipsychotics. Individualized titration, regular patient and care partner feedback, and functional, rather than purely motor-based, assessments are key to optimizing therapy. By integrating pharmacologic therapy with multidisciplinary care and holistic, goal-oriented communication about the impact of chorea, clinicians can meaningfully improve safety, independence, and quality of life for individuals and families affected by HD.
BackgroundSleep disturbances, including fragmentation and reduced slow-wave sleep (SWS), are common in Huntington's disease (HD). SWS contributes to synaptic homeostasis, metabolic clearance, and memory consolidation. Phase-targeted auditory stimulation (PTAS) enhances slow-wave activity (SWA) in healthy individuals and Parkinson's disease, but its feasibility and physiological effects in HD remain unknown.ObjectiveTo assess the feasibility and physiological effects of PTAS in individuals with HD in a home-based setting.MethodsTen participants with genetically confirmed HD were enrolled in a randomized, double-blind, sham-controlled crossover pilot study conducted at home. After a test night, participants completed one sham and one verum night using a wearable sleep device. Auditory stimuli (pink-noise bursts) were delivered in alternating 6-s ON and OFF windows targeting the up-phase of slow waves during non-rapid eye movement sleep. SWA (0.5-4.5 Hz) and frequency-resolved EEG power were analyzed using linear mixed-effects models.ResultsFive participants completed the protocol and were included in the analysis. Four showed higher SWA during ON compared with OFF windows during verum nights. Frequency-resolved analyses demonstrated increased delta-band power during ON windows relative to sham. No relevant differences in sleep macrostructure were observed between verum and sham nights, although interpretation was limited by the small sample size and participant heterogeneity. Completion was limited by device discomfort, external factors, and technical issues.ConclusionPTAS transiently enhances SWA during stimulation windows in some individuals with HD in an at-home setting. Larger studies are needed to identify predictors of response and determine clinical relevance.
ObjectiveTo compare the sensitivity of the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) for detecting cognitive change in Huntington's disease (HD) subjects stratified by baseline performance quartiles and the Huntington's Disease Integrated Staging System (HD-ISS).MethodsParticipants (age 25-65; CAG 40-50) from an observational cohort completed MMSE and MoCA at baseline, with follow-up visits at least six months after baseline, and observations truncated at five years.We analyzed the full cohort (n = 246) and an HD-ISS-staged subset (n = 132). Longitudinal change was evaluated using mixed-effects models, adjusted for baseline age, gender, education, CAG, and age × CAG interaction. Baseline discrimination between HD-ISS stages was assessed with ROC curves and AUC comparisons.ResultsAnnual decline was nearly identical for MMSE and MoCA (-0.334 vs. -0.331). Adjusted quartile analyses revealed differential sensitivity: MoCA showed greater decline in lower and higher performance levels (Quartiles 1, 3, and 4), while MMSE was most sensitive at mid-range (Quartile 2). In HD-ISS analyses, MMSE demonstrated more consistent decline across stages, particularly Stages 1 and 3, indicating sensitivity to early and moderate disease phases. Baseline ROC analyses favored MoCA for stage discrimination (Stage 0 vs. all: AUC 0.789 vs. 0.686, p = 0.011).ConclusionThe MMSE and MoCA exhibit complementary strengths. MoCA demonstrates superior sensitivity for baseline staging and early disease detection, while MMSE better captures longitudinal decline. These findings suggest that combined use of both instruments may provide a more complete assessment of cognitive progression in HD.
Age of onset in Huntington disease (HD) is influenced by cis-acting genetic variants, particularly the loss of interrupting codons in the HTT CAG and CCG repeats (CAG-CCG LOI variant). The CAG-CCG LOI variant is not detectable by current diagnostic assays, leading to underestimation of CAG repeat length, misdiagnosis, and inaccurate prediction of risk of symptom onset in the reduced penetrance range. In clinical trials, unidentified CAG-CCG LOI variants may affect interpretation of results, particularly for small trials. Accurate ascertainment and reporting of the CAG-CCG LOI genotype therefore has important implications for HD diagnosis, genetic counselling, and clinical trial design.
Huntington's disease (HD) is a progressive, inherited neurodegenerative condition that imposes a profound, multidimensional burden on individuals with HD and their families. This qualitative study explored the physical, emotional, socioeconomic, and intergenerational impact of HD across six European countries, drawing on interviews with individuals diagnosed with HD and family caregivers. Findings reveal that HD disrupts daily functioning, employment, relationships, and long-term planning. Cognitive and psychiatric symptoms were particularly burdensome, driving declines in quality of life (QoL) and emotional well-being. Caregivers reported extensive physical, financial, and psychological strain, with many assuming care responsibilities from a young age or eventually caring for multiple relatives. These burdens frequently spanned generations, with participants describing how HD shaped their upbringing, reproductive choices, and expectations for future caregiving. Despite some optimism regarding future research, participants expressed concern that therapeutic advances would not arrive in time to benefit them, reinforcing the urgency for non-pharmacological support. There was strong support for more accessible, consistent, and family-centred care models that integrate clinical services with psychosocial and financial supports. Participants emphasized the importance of early diagnosis, proactive care planning, and coordinated support networks to mitigate caregiver burden and improve long-term outcomes. These findings underscore the need for healthcare systems and policies to move beyond symptom management and address HD as a multigenerational, systemic challenge which needs to be met with a holistic model of care responsive to the evolving needs of both patients and caregivers.
Huntington's disease (HD) patients with anterior cingulate cortex atrophy typically exhibit mood symptomatology. However, the midcingulate cortex's (MCC) role in HD is poorly understood. mRNA sequencing was utilized to examine the MCC transcriptome in HD, and differentially expressed transcripts were validated by NanoString analysis. Transcriptomic analysis of 14 HD patients exhibiting mood, motor, or mixed symptoms revealed differential expression of 223 genes, including several homeo-domain, developmental, and noncoding genes in the MCC. Protein-protein interaction, gene ontology, and cell-type enrichment analyses identified dysregulated pathways in the adult MCC involved in processes linked to embryonic development and organogenesis, epigenetic modification, transcription regulation, neuronal differentiation, and motor system development. Key findings include misexpressed genes associated with limb, muscle and motor neuron development in the motor cohort. These alterations suggest that mutant huntingtin may influence developmental processes via aberrant WNT (Wingless), REST (RE1-silencing transcription factor), and transcription factor signaling, potentially affecting MCC motor function circuitry and neuronal maturation. This study indicates a developmentally associated transcriptional signature in the adult HD MCC that may contribute to altered neuronal function.
Somatic instability (SI) of the CAG tract in HTT is a major driver of neurodegeneration of Spiny Projection Neurons (SPNs), the primary neuronal subtype affected in Huntington's disease (HD). SPNs can accumulate hundreds of CAG repeats during a patient's lifetime, and once the expansion exceeds ∼150 CAGs, they acquire distinct, cell-autonomous transcriptional alterations that ultimately contribute to degeneration. Here, we developed the “HD-Phase-Model”, a mathematical framework designed to identify “super-expanded” SPNs without repeat sizing, by leveraging the only available single-nucleus HD post-mortem dataset that provides both transcriptional profile and matched HTT CAG sizes. After validating model performance on the test data, we applied it to independent single-nucleus datasets lacking CAG sizing information and across multiple brain regions. In all cases, the model consistently detected SPNs populations with convergent transcriptional dysregulation signatures indicative of extreme CAG expansion. Importantly, although the model was trained on caudate SPNs, we observed highly similar dysregulation patterns in putamen and accumbens, while no evidence of super-expansion was found in SPNs from Alzheimer's and Parkinson's disease donors. Together, these findings demonstrate that transcriptional profiles alone can serve as predictors of HTT CAG size, enabling systematic identification of super-expanded SPNs and providing insights into HD-specific neurodegenerative mechanisms.
Huntingtin (HTT) is an essential pleiotropic gene. Primarily known for its pathogenic role in Huntington's disease (HD), a progressive autosomal dominant neurodegenerative disorder. HD is caused by a CAG expansion located in HTT exon 1 that produces an altered protein product, mutant huntingtin, with an expanded polyglutamine stretch. Despite its monogenic origin, HD has a complex cellular pathology likely due to huntingtin's many protein-protein interactions and diverse functional roles. Wild-type huntingtin loss-of-function may influence HD pathogenesis by intertwining with multiple forms of mutant huntingtin gain-of-function toxicity. Multiple studies have identified irregular neurodevelopmental phenotypes in HD models similar to those due to wild-type huntingtin loss-of-function. Current huntingtin lowering treatment developments suggest that a better understanding of normal HTT functions may be vital for effective therapeutic development. Due to the history of huntingtin gene discovery, most previous reviews have focused on the wild-type huntingtin allele in the context of also inheriting the mutant huntingtin allele. The purpose of this review is to explore wild-type huntingtin's putative function, expression, and variation in neurodevelopment in the absence of the mutant HTT allele, providing a basis to better understand how changes in wild-type huntingtin function may play a role in human health and disease.
Background Weight loss and eating difficulties are common in Huntington's disease (HD), but professionals' perspectives remain underexplored.Objective To investigate professionals and service users' perspectives on weight loss and eating difficulties, and explore how these issues are prioritized, managed, and experienced.Methods Semi-structured interviews (n = 19; 10 professionals, 9 service users) in the UK. Reflexive thematic analysis identified key themes regarding the causes, management, and impact of eating problems in HD.Results Six themes emerged: (1) Common tactics for weight gain and their limitations, (2) Variability in professional knowledge and access to care, (3) Cognitive and psychopathological contributors to weight loss, (4) Physical and practical barriers to eating, (5) Social and emotional impacts of feeding difficulties, and (6) Perceptions of weight loss and disease progression. Within these themes we found that, amongst other findings, high-energy diets and supplements are widely used but often poorly tolerated long-term. Access to specialist care is inconsistent, leading to a "geographical lottery". Cognitive and psychological symptoms, including apathy and executive dysfunction, significantly affect eating behaviors. Physical symptoms such as chorea and dysphagia further complicate intake. Social withdrawal due to embarrassment is common. Weight loss is often under-recognized or under-prioritized by patients.Conclusions Causes of weight loss are complex and need multidisciplinary holistic management, which is not always available. Management of complex psychosocial factors is as important as managing physical symptoms. Proactive, personalized interventions can improve both longevity and quality of life for people with HD.
BACKGROUND/OBJECTIVE:This study extends prior clinimetric evaluations by examining the factor structure, internal consistency, and distributional properties of the Problem Behaviors Assessment - Short Form (PBA-s) in a large sample of people with Huntington's disease (pwHD) at various stages of progression using the Huntington's Disease Integrated Staging System (HD-ISS) framework. METHODS:Baseline PBA-s item total scores were analyzed from 14,371 Enroll-HD participants. Using HD-ISS criteria, participants were categorized as Stage 0/1 (n = 3262; 23%), Stage 2 (n = 1722; 12%), or Stage 3 (n = 9387; 65%). RESULTS:Missing responses were low across items and stages. Item total score distributions demonstrated significant skew in Stages 0/1 and 2. Within Stage 3, skewness was less prevalent but still present in most distributions. In all groups, the PBA-s demonstrated moderate internal consistency, though five items exhibited weak item-total correlations. Resultant factor structures differed from those previously reported and varied by HD-ISS stage. In Stages 0/1 and 2, a three-factor model representing internalizing, externalizing, and cognitive control problems accounted for 39-42% of the total variance. In Stage 3, a five-factor solution explained 56% of the overall variance and consisted of internalizing, externalizing, cognitive control problems, suicidality, and cognitive dysfunction. CONCLUSIONS:While the PBA-s demonstrates adequate internal consistency, our results revealed high rates of non-endorsement (i.e., item total scores = 0) and a variable factor structure with disease progression. Thus, the PBA-s may not distinguish mild changes in behavioral symptoms that might occur in early HD-ISS stages of disease.
