Journal of Huntington's disease最新文献_第5页

Huntington's as a developmental disorder: Molecular and neuropathologic considerations. 亨廷顿舞蹈症作为一种发育障碍：分子和神经病理学的考虑。

IF 3.1

Journal of Huntington's disease Pub Date : 2026-05-01 Epub Date: 2025-11-18 DOI: 10.1177/18796397251395783

Mallory R Shin, Marco M Hefti

{"title":"Huntington's as a developmental disorder: Molecular and neuropathologic considerations.","authors":"Mallory R Shin, Marco M Hefti","doi":"10.1177/18796397251395783","DOIUrl":"10.1177/18796397251395783","url":null,"abstract":"Huntington's disease (HD) is classically characterized as a late-onset neurodegenerative disorder of adulthood caused by CAG expansion in the HTT gene. However, mounting evidence from both human and experimental studies suggests that both wild-type and mutant huntingtin play important roles during brain development. In this review, we examine the developmental functions of huntingtin, including its role in neuronal migration, synaptogenesis, suppression of apoptosis, mitotic spindle orientation, and transcriptional regulation. We also discuss how mutant HTT may act through both loss- and gain-of-function mechanisms during early brain development. Comparative evolutionary analysis suggests that HTT is highly conserved and that the emergence of the N-terminal polyglutamine tract may have conferred developmental advantages in organisms with more complex nervous systems. Interestingly, studies in pre-symptomatic human carriers and mouse models have identified potential early-life cognitive benefits associated with moderate CAG expansion, raising the possibility of antagonistic pleiotropy. Understanding huntingtin's dual function in neurodevelopment and degeneration is essential in gaining insights into the earliest stages of HD pathogenesis, long before clinical onset.","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"226-234"},"PeriodicalIF":3.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145549560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Abnormal neurodevelopment predisposes to cortical hyperexcitability in Huntington's disease. 亨廷顿氏病患者神经发育异常易导致皮质亢进。

IF 3.1

Journal of Huntington's disease Pub Date : 2026-05-01 Epub Date: 2025-08-19 DOI: 10.1177/18796397251366891

Carlos Cepeda, Joshua Barry, Sandra M Holley

{"title":"Abnormal neurodevelopment predisposes to cortical hyperexcitability in Huntington's disease.","authors":"Carlos Cepeda, Joshua Barry, Sandra M Holley","doi":"10.1177/18796397251366891","DOIUrl":"10.1177/18796397251366891","url":null,"abstract":"Accumulating morphological and electrophysiological evidence demonstrates that abnormal brain development is a key element in the progression of Huntington's disease (HD). Mutant huntingtin affects corticogenesis, cell migration, and differentiation. Cortical changes are reminiscent of focal cortical dysplasia, a malformation of cortical development that leads to hyperexcitability and epilepsy. Striatal development also is affected by the mutation. In animal models, recent studies provide additional evidence that neuronal morphology and intrinsic and electrophysiological properties deviate from normal development. Some changes indicate delayed development of cortical pyramidal neurons, while a subtype of striatal projection neuron displays a transient accelerated maturation. However, the brain is able to compensate for early abnormalities and, during a variable latent period, brain function appears normal. Eventually, homeostatic mechanisms begin to fail, resulting in the emergence of HD symptoms. The realization that neurodevelopment in HD is abnormal offers new insights and opens new avenues for early treatment. In this review, we present a brief summary of imaging and morphological studies from human carriers of the HD mutation followed by a more in-depth examination of recent findings in genetic animal models.","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"190-200"},"PeriodicalIF":3.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Contribution of neuroepigenetics to HD - developmental and aging-related signatures. 神经表观遗传学对HD发育和衰老相关特征的贡献。

IF 2.7

Journal of Huntington's disease Pub Date : 2026-05-01 Epub Date: 2026-02-27 DOI: 10.1177/18796397261426625

Jil Scuto, Noémie Penaud, Karine Merienne

{"title":"Contribution of neuroepigenetics to HD - developmental and aging-related signatures.","authors":"Jil Scuto, Noémie Penaud, Karine Merienne","doi":"10.1177/18796397261426625","DOIUrl":"10.1177/18796397261426625","url":null,"abstract":"Huntington's disease (HD) is a neurodegenerative disorder triggered by an unstable expansion of CAG repeats in the coding sequence of the HTT gene. Among the neuronal populations affected, striatal spiny projection neurons (SPNs) show particular susceptibility to the pathogenic mutation. The basis of this selective vulnerability, however, is still not fully understood. In this review, we highlight recent epigenomic research on HD, framing it within current concepts in epigenetics. We propose that epigenetic regulation contributes to neuronal vulnerability in HD. Functional genomics studies provide growing evidence in support of this view. Findings from both HD animal models and patient-derived tissues have shown somatic CAG expansion-dependent epigenetic and transcription erosion in vulnerable neurons, which leads to accelerated loss of the identity of vulnerable neurons, promoting their premature aging. Moreover, HD stem cell models show that epigenetic and transcriptional alterations also occur during neural differentiation, impacting neuronal specification and maturation trajectories. This suggests that abnormal epigenetic priming during neurodevelopment might further predispose vulnerable neurons to later epigenetic and transcriptional erosion, thereby amplifying their susceptibility in the disease.","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"263-274"},"PeriodicalIF":2.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147306977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Wild-type huntingtin in neurodevelopment. 神经发育中的野生型亨廷顿蛋白。

IF 2.7

Journal of Huntington's disease Pub Date : 2026-05-01 Epub Date: 2026-04-09 DOI: 10.1177/18796397251410442

Laura Lynn Chan, Blair R Leavitt

{"title":"Wild-type huntingtin in neurodevelopment.","authors":"Laura Lynn Chan, Blair R Leavitt","doi":"10.1177/18796397251410442","DOIUrl":"10.1177/18796397251410442","url":null,"abstract":"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.","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"252-262"},"PeriodicalIF":2.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Preface to special issue on neurodevelopment in Huntington's disease. 关于亨廷顿舞蹈病神经发育的特刊前言。

IF 3.1

Journal of Huntington's disease Pub Date : 2026-05-01 Epub Date: 2026-05-27 DOI: 10.1177/18796397261453708

Blair R Leavitt, Leslie M Thompson

引用次数: 0

Early life functional advantage coupled with accelerated aging: The case for antagonistic pleiotropy in Huntington's disease. 早期生命功能优势与加速衰老相结合：亨廷顿病的拮抗多效性病例。

IF 3.1

Journal of Huntington's disease Pub Date : 2026-05-01 Epub Date: 2025-11-05 DOI: 10.1177/18796397251391069

Jordan L Schultz, Peg C Nopoulos

{"title":"Early life functional advantage coupled with accelerated aging: The case for antagonistic pleiotropy in Huntington's disease.","authors":"Jordan L Schultz, Peg C Nopoulos","doi":"10.1177/18796397251391069","DOIUrl":"10.1177/18796397251391069","url":null,"abstract":"Recent findings suggest that neurodevelopment plays a critical role in Huntington's Disease (HD) pathogenesis. This review integrates data from human studies of children and young adults at risk for HD (the Kids-HD study) with the theory of antagonistic pleiotropy (AP), which posits that genes promoting early-life advantages may confer late-life risks. Longitudinal imaging of gene-expanded (GE) children and adolescents shows that mHTT is associated with larger cortical volumes, enhanced surface morphology, and superior cognitive performance-decades before clinical onset. However, this early benefit is paired with accelerated striatal decline, suggesting that mHTT drives an early \"ability\" that transitions into a \"liability.\" Vertex-wise analyses reveal cortical enlargement in regions with dense glutamatergic projections to the striatum, implicating excitotoxicity as a mechanism linking development to degeneration. This pleiotropic pattern parallels evolutionary models, where genes like HTT may have an evolutionary trade-off where genes supporting growth and reproduction are favored over those that serve long-term somatic maintenance, leaving cells with diminished repair capacity and resulting in an accelerated aging process. Altogether, these findings support a novel framework in which mHTT accelerates both brain maturation and neurodegeneration, offering new insights into HD biology and therapeutic targets.","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"201-213"},"PeriodicalIF":3.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145444958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Introduction to special issue: neurodevelopment in huntington's disease. 特刊导论：亨廷顿舞蹈病的神经发育。

IF 3.1

Journal of Huntington's disease Pub Date : 2026-05-01 Epub Date: 2026-04-01 DOI: 10.1177/18796397261436145

Peggy C Nopoulos, Elena Cattaneo

引用次数: 0

Mouse models to interrogate the developmental pathogenesis of Huntington's disease. 小鼠模型探讨亨廷顿氏病的发育发病机制。

IF 2.7

Journal of Huntington's disease Pub Date : 2026-05-01 Epub Date: 2026-01-08 DOI: 10.1177/18796397251412135

Yagiz M Altun, Siyu Yan, Kevin Zheng, Aldrin E Molero, Mark F Mehler

{"title":"Mouse models to interrogate the developmental pathogenesis of Huntington's disease.","authors":"Yagiz M Altun, Siyu Yan, Kevin Zheng, Aldrin E Molero, Mark F Mehler","doi":"10.1177/18796397251412135","DOIUrl":"10.1177/18796397251412135","url":null,"abstract":"Huntington's disease (HD) has traditionally been viewed as a late-onset neurodegenerative disorder. However, emerging evidence suggests that differences in the stoichiometry of wild-type huntingtin (HTT) and mutant huntingtin (mHTT) exert a complex spectrum of pathogenic effects during early brain development, preceding the onset of overt clinical signs by several decades. In this review, we examine how various HD mouse models have revealed distinct yet frequently converging developmental abnormalities through the dynamic interplay of novel early pathogenic and homeostatic processes. Full-length transgenic models like BACHD demonstrate early glial dysmaturation, corticostriatal synaptic deficits, and behavioral phenotypes emerging during infancy. Truncated fragment models such as R6/2 exhibit aggressive phenotypes resembling juvenile HD, with early neuronal and myelination defects. Knock-in models, including HdhQ111, HdhQ140, and zQ175, highlight CAG-length-dependent disruptions in neural progenitor cell dynamics, synaptic formation, and cortical plasticity. Loss-of-function models further implicate wild-type HTT in neural patterning and germ layer specification, recapitulating HD-like features in the absence of mHTT overexpression. Together, these models underscore a developmental dimension to HD pathogenesis and suggest that early-life circuit miswiring, glial dysfunction, and impaired integrity of the specification, maturation, and maintenance of neural cell identity and functions may prime the brain for later neurodegeneration. Understanding these early disruptions is essential for identifying novel early therapeutic windows, biomarkers, and molecular targets essential for devising true disease-modifying paradigms aimed at delaying, reversing, or even preventing the onset of disease hallmarks.","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"235-251"},"PeriodicalIF":2.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145933751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Insights into neurodevelopmental features of Huntington's disease from stem cell-derived models including organoids. 从包括类器官在内的干细胞衍生模型深入了解亨廷顿氏病的神经发育特征。

IF 2.7

Journal of Huntington's disease Pub Date : 2026-05-01 Epub Date: 2025-12-12 DOI: 10.1177/18796397251399701

Mariana Sierra, Rachael Powers, Nikolas Grotewold, Henry Paulson

{"title":"Insights into neurodevelopmental features of Huntington's disease from stem cell-derived models including organoids.","authors":"Mariana Sierra, Rachael Powers, Nikolas Grotewold, Henry Paulson","doi":"10.1177/18796397251399701","DOIUrl":"10.1177/18796397251399701","url":null,"abstract":"Two- and three-dimensional (2D and 3D) cell models derived from human stem cells have shed light on a wide range of molecular and cellular features of Huntington's disease (HD). Here we review the use of human stem cell-derived models to explore neurodevelopmental contributions to HD. We provide a timeline of key advances made in 2D and 3D model systems, ranging from differentiated monocultures to brain-like organoids and assembloids. Models along this spectrum have advanced our understanding of various disease-associated characteristics including disease protein (huntingtin) aggregation, somatic repeat instability, transcriptional dysregulation, perturbations in neurodevelopmental staging, and neural circuitry. We highlight recent findings in brain-like organoids which, despite being a relatively recent innovation, are proving to be a promising tool with which to study aberrant neurodevelopmental features of HD. All models have their limitations, and we compare and contrast the utility and limitations of various stem cell-based methods to study HD. Finally, we speculate on future advances employing advanced computational and transcriptomic methods that will expand the power of 3D model systems for the study of HD and related neurodegenerative disorders.","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"214-225"},"PeriodicalIF":2.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12910477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145742316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The clinical phenotype of carriers of intermediate alleles in the huntingtin gene: A scoping review. 亨廷顿基因中间等位基因携带者的临床表型：范围综述。

IF 3.1

Journal of Huntington's disease Pub Date : 2026-02-01 Epub Date: 2025-12-17 DOI: 10.1177/18796397251397683

Anna van Hofslot, Mayke Oosterloo, Joost J A de Jong, Ruben L Andriessen, Susanne T de Bot, David E J Linden

{"title":"The clinical phenotype of carriers of intermediate alleles in the huntingtin gene: A scoping review.","authors":"Anna van Hofslot, Mayke Oosterloo, Joost J A de Jong, Ruben L Andriessen, Susanne T de Bot, David E J Linden","doi":"10.1177/18796397251397683","DOIUrl":"10.1177/18796397251397683","url":null,"abstract":"BackgroundHuntington's Disease (HD) is a hereditary neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion (CAG > 35) in the Huntingtin (HTT) gene. Intermediate alleles (IAs, CAG = 27-35) are generally not associated with HD. However, IA carriers with symptoms have been reported in literature.ObjectiveTo review the existing literature on IAs, in order to provide an overview of the clinical phenotype of IA carriers.MethodsPeer-reviewed articles published between 1993 and July 2024 from three databases (Embase, PubMed, and Web of Science) were included.ResultsIn case reports, a high percentage (90%) of IA carriers was reported to have symptoms (HD-related and -unrelated), or abnormalities in neuroimaging. Cohort studies also reported evidence of symptoms in IA carriers, although most cohorts did not obtain significant differences compared to controls.ConclusionBased on this review, we argue that there is not enough evidence to draw a clear conclusion on the clinical phenotype of individuals carrying an intermediate allele of the HTT gene. Literature reports symptomatic IA carriers, but reported symptoms are non-specific and common in the general population. Additionally, the quality of the data is suboptimal, due to lack of detailed symptom descriptions, the absence of differential diagnoses, a selection bias, and a considerable publication bias towards IA carriers with symptoms. More research is needed to provide a better insight into the clinical phenotype of IA carriers.","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":" ","pages":"3-19"},"PeriodicalIF":3.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12847463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145774449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0