Advances in Pathogenesis, Biomarkers, and Therapeutic Development in Huntington’s Disease
A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".
Deadline for manuscript submissions: 31 May 2026 | Viewed by 20
Special Issue Editor
2. Medicine Department, Universitat Autònoma de Barcelona (UAB), 08193 Barcelona, Spain
Interests: Huntington’s disease; neurodegeneration; molecular biomarkers; neuroimaging; disease-modifying therapies; RNA biology; genetic and epigenetic mechanisms; motor; neuropsychiatric and cognitive impairment mechanisms
Special Issue Information
Dear Colleagues,
Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene, leading to the production of mutant huntingtin and progressive motor, cognitive, and psychiatric decline. In recent years, research has increasingly focused on the molecular determinants of disease onset and progression, including the role of genetic modifiers, DNA repair pathways, and somatic CAG repeat expansion, which critically influence penetrance, age at onset, and disease trajectory.
Key advances across multiple biological domains have reshaped our understanding of HD pathogenesis, revealing intricate interactions involving aberrant protein homeostasis, RNA toxicity, transcriptional dysregulation, impaired axonal transport, mitochondrial dysfunction, excitotoxicity, synaptic failure, and neuroinflammatory responses. Moreover, increasing evidence indicates that the underlying biology of the disease varies substantially across individuals, contributing to the heterogeneous cognitive, behavioral, and motor phenotypes observed in HD. The mechanisms driving this inter-individual variability, and how they influence distinct progression patterns, remain poorly understood and warrant further investigation.
In parallel, therapeutic innovation—including HTT-lowering strategies using antisense oligonucleotides (ASOs); RNA interference approaches (RNAi/siRNA); splicing modulation to prevent HTTexon1 formation; RNA-targeting compounds; and emerging gene-editing platforms such as CRISPR/Cas systems, TALENs, and zinc-finger protein-based therapies—continues to expand the translational landscape. Achieving mechanistic clarity, robust target engagement, and validated biomarkers is essential for advancing disease-modifying treatments.
This Special Issue aims to gather high-quality contributions that expand our molecular, cellular, clinical, and translational understanding of Huntington’s disease. We welcome submissions addressing the following:
- Genetics, genetic modifiers, and somatic instability, including DNA repair pathways and modifiers of disease onset and progression.
- Mechanistic studies on mutant huntingtin, protein–protein and protein–RNA interactions.
- Transcriptional, epigenetic, and splicing dysregulation, including the biology and pathogenic role of HTTexon1.
- Biomarker development in CSF, plasma, neuroimaging, electrophysiology, and digital endpoints.
- Preclinical models, including iPSC-derived neurons, glia, and organoids.
- Therapeutic discovery, target identification, and mechanism-of-action studies.
- Neurobiology of clinical manifestations, including
- Motor manifestations (chorea, dystonia, motor impersistence, bradykinesia, gait disturbances, and underlying physiological mechanisms);
- Behavioral and psychiatric disturbances (apathy, depression, irritability, impulsivity, psychosis);
- Cognition and dementia (early cognitive decline, disease staging, mechanistic correlates of impairment);
- Systemic features (metabolic, endocrine, autonomic, and peripheral involvement).
- Advances in translational research and clinical trial methodology.
We hope this Special Issue will foster interdisciplinary collaboration, deepen mechanistic insight, and accelerate the development of effective disease-modifying therapies for Huntington’s disease.
Dr. Jesús Pérez-Pérez
Guest Editor
Manuscript Submission Information
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Keywords
- Huntington’s disease
- somatic instability
- genetic modifiers
- HD RNA biology
- mutant huntingtin
- molecular pathogenesis
- biomarkers
- neurobiology of chorea
- cognition and psychiatric disturbances
- HTT-lowering therapies, gene therapy
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