HDDF2—A Novel Patient-Derived Fibroblast Line from Huntington’s Disease with Prominent Cellular Senescence and polyQ Pathology

Background/Objectives: Patient-derived cell lines retaining donor-specific age-related and genomic features are essential for modeling late-onset neurodegenerative disorders like Huntington’s disease (HD). This study aims to establish and comprehensively characterize HDDF2, a novel dermal fibroblast line from an HD patient, to provide a relevant cellular model. Methods: Dermal fibroblasts were isolated and cultured from a 44-year-old male HD patient carrying 46 CAG repeats in the HTT gene. Cells were evaluated for senescence markers (p16, lamin B1, SA-β-Gal activity, proliferation rates) and polyglutamine (polyQ) aggregation. Direct reprogramming protocols were applied to convert these fibroblasts into induced neurons. Results: HDDF2 fibroblasts exhibited a pronounced senescence-associated phenotype, evidenced by increased p16 expression, reduced lamin B1 levels, elevated SA-β-Gal activity, and decreased proliferation. Notably, polyQ deposition was preferentially detected within the senescent subpopulation, displaying distinct localization patterns differentiating senescent from proliferating cells. Despite this, HDDF2 cells retained their capacity for direct reprogramming and were successfully converted into induced neurons. Conclusions: HDDF2 represents a well-characterized, patient-specific cellular model for HD. The observed co-occurrence of polyQ deposition and cellular senescence, combined with successful neuronal conversion, establishes this line as a valuable resource for investigating the relationship between cellular aging and HD pathogenesis.