Elevated levels of mosaic aneuploidy in brain cells and fibroblast cell lines from human Huntington’s disease donors and in brain cells from Huntington’s disease mouse models

Abstract

AbstractBackgroundHuntington’s disease (HD) is a progressive neurodegenerative disorder that presents with motor and cognitive deficits and psychiatric disturbances. HD is associated with autosomal dominant inheritance of a CAG trinucleotide repeat expansion mutation in the huntingtin (HTT) gene. The huntingtin protein localizes to spindle poles and is required for proper mitotic spindle orientation, chromosome segregation, and cell cycle regulation. The mature mutant huntingtin protein has an expanded polyglutamine region (>35 repeats) near its N terminus, which leads to neuronal dysfunction and death. Mouse models of HD exhibit defects in microtubule function and cell cycle regulation. Studies from our laboratory and others have shown elevated levels of aneuploidy in many neurodegenerative disorders characterized by cognitive deficits, including Alzheimer’s disease and frontotemporal lobar degeneration. Here, we investigated whether chromosome segregation defects that lead to mosaic aneuploidy and consequent apoptosis may also contribute to neuronal loss in HD.MethodsSingle‐cell suspensions from cortex and cerebellum from human HD donors were analyzed using FISH for chromosome 21, NeuN immunostaining, and/or TUNEL staining. Fibroblast cell lines from human HD donors were also analyzed using FISH. Single‐cell suspensions from cortex and cerebellum from HD mouse models were analyzed using FISH for chromosomes 5 and 16. Cell cycle arrest, mitotic spindle defects, ploidy, and apoptosis profiles in the HD fibroblast cell lines are being analyzed by flow cytometry and immunofluorescence microscopy.ResultsIncreased levels of mosaic aneuploidy and apoptosis were observed in brain cells and in fibroblast cell lines from HD donors compared to age‐matched healthy control donors. Increased levels of mosaic aneuploidy were also observed in brain cells from HD mice compared to age‐matched wild‐type control mice. Results of ongoing studies of cell cycle and mitotic defects will also be presented.ConclusionsTaken together with the results of our previous studies, these data provide evidence that chromosome segregation defects that lead to genomic instability may serve as a shared mechanism underlying many neurodegenerative disorders. Our findings highlight the need to further investigate the biological mechanism(s) that contribute to HD pathology and set the stage for novel therapeutic approaches to HD that may also be applied to other neurodegenerative disorders.