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Cavadas, C.

Publications and source records attributed to Cavadas, C..

2 recordsLinked to original sources
bioRxiv2023

Nuclear aging in polyglutamine-induced neurodegeneration

Machado-Joseph disease (MJD) is an autosomal dominantly-inherited neurodegenerative disorder characterized by an over-repetition of the CAG trinucleotide of the ATXN3 gene, 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 Alzheimers, Huntingtons, 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 Alzheimers 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.

neuroscience↗
bioRxiv2023

Ghrelin delays premature aging in Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal genetic condition arising from a single nucleotide alteration in the LMNA gene, which leads to the production of a defective lamin A protein known as progerin. The buildup of progerin hastens the onset of premature and expedited aging. Patients with HGPS exhibit short stature, low body weight, lipodystrophy, metabolic dysfunction, and skin and musculoskeletal abnormalities and, in most cases, die of cardiovascular disease by their early teenage years. Currently, no effective cure or treatment for the disease highlights the importance of discovering new therapeutic strategies. Herein, we present evidence that the hormone ghrelin, besides promoting autophagy and progerin clearance, rescued several cellular hallmarks of premature aging of human HGPS fibroblasts. Using an HGPS mouse model, LmnaG609G/G609G mice, we also show that ghrelin administration rescued the short-lived mice molecular and histopathological progeroid features, prevented progressive weight loss at later stages, reverted the lipodystrophic phenotype, and extended lifespan. Thus, we disclose that modulation of ghrelin signaling may give rise to new treatment targets and translational approaches that may improve outcomes and the health quality of HGPS patients and natural aging pathologies.

physiology↗