Nuclear aging in polyglutamine-induced neurodegeneration

Abstract

AbstractMachado-Joseph disease (MJD) is an autosomal dominantly-inherited neurodegenerative disorder characterized by an over-repetition of the CAG trinucleotide of theATXN3gene, conferring a toxic gain-of-function to the resulting ataxin-3 protein. Despite the significant advances produced over the last years, the molecular mechanisms involved in MJD are still unclear and no treatment able to modify the disease progression is available. Aging is the major risk factor for neurodegenerative disorders, being associated with the occurrence and progression of several diseases, such as Alzheimer’s, Huntington’s, among others. The nuclear membrane proteins - lamins - and lamin-processing related proteins, such as ZMPSTE24, have been shown to be altered, not only during normal aging, but also in neurodegenerative disorders, such as Alzheimer’s disease.Taking this into account, we aimed at investigating the role of aging in MJD by evaluating the presence of age-related markers in human and animal MJD models. Decreased levels of lamins B and C, together with decreased ZMPSTE24 levels were identified in the different MJD models. Accordingly, abnormalities in nuclear circularity, a hallmark of aging, were also observed in a N2a MJD cellular model, supporting an age-related phenotype. Furthermore, overexpressing progerin, the abnormal lamin A, generated in Hutchinson Guilford Progeria Syndrome patients that present premature and accelerated aging, in a relevant brain area of a lentiviral MJD mouse model, induced an aggravation of MJD-associated neuropathology.Our results suggest that aging is a key player in the context of MJD pathogenesis, unveiling new pathways for the development of future therapies for the disease.