Nuclear aging in polyglutamine-induced neurodegeneration
Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder caused by a CAG over-repetition in the ATXN3 gene, resulting in a toxic gain-of-function in the ataxin-3 protein. Despite all the advances, its molecular mechanisms remain unclear, and no disease-modifying treatments are available. Aging is the major risk factor for neurodegenerative diseases, including Alzheimer’s an
Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder caused by a CAG over-repetition in the ATXN3 gene, resulting in a toxic gain-of-function in the ataxin-3 protein. Despite all the advances, its molecular mechanisms remain unclear, and no disease-modifying treatments are available. Aging is the major risk factor for neurodegenerative diseases, including Alzheimer’s and Huntington’s. Nuclear membrane proteins (lamins) and related processing proteins like ZMPSTE24 are altered not only in aging but also in neurodegeneration. To explore aging’s role in MJD, we examined age-related markers in human and animal MJD models. Reduced levels of lamins B, C and ZMPSTE24 were observed, along with nuclear shape abnormalities - hallmark of aging. Additionally, overexpressing progerin (mutant lamin A that causes premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS)) in a relevant brain area of a lentiviral MJD mouse model, aggravated MJD-related neuropathology. These findings suggest that aging mechanisms may contribute to MJD progression, offering potential targets for therapy.