Biology subjects

Sola, A.

Publications and source records attributed to Sola, A..

2 recordsLinked to original sources

bioRxiv2025

Polyamine biosynthesis dysregulation in Alzheimer's disease and Down syndrome cellular models

BACKGROUNDIndividuals with Down Syndrome (DS) frequently develop early onset Alzheimers disease (AD) with pathological hallmarks closely resembling AD due to several triplicated genes on chromosome 21. Polyamines are small, organic molecules that play a pivotal role for growth and differentiation, and a dysregulation of polyamine pathways is implicated in AD pathology. However, their role in DS-associated AD is unclear. METHODSWe analyzed polyamines and their metabolite levels in mouse hippocampal cells and human DS-AD and AD hippocampal tissue and assessed the effects of the ODC inhibitor difluoromethylornithine (DFMO) on A{beta}42 aggregation and protein expression in DS fibroblasts. RESULTSAmyloid-{beta}42 increased polyamine levels via ornithine decarboxylase (ODC) activation in a dose-dependent manner. DFMO reduced A{beta}42 aggregation, decreased amyloid precursor protein (APP) levels, and normalized proteins linked to AD pathology in DS fibroblasts. Polyamine levels were elevated in DS-AD hippocampal tissue, with colocalization of ODC and A{beta}42 aggregates. CONCLUSIONThese findings suggest that polyamine biosynthesis may exacerbate A{beta}42 toxicity and APP expression, contributing to AD progression in DS. The ability of DFMO to reduce A{beta}42 aggregation and restore protein homeostasis presents the polyamine pathway as a therapeutic target for DS-AD management.

biochemistry↗

bioRxiv2022

Iron accumulation drives fibrosis, senescence, and the senescence-associated secretory phenotype

Fibrogenesis is part of a normal protective response to tissue injury that can become irreversible and progressive, leading to fatal diseases. Senescent cells are a main driver of fibrotic diseases through their secretome, known as senescence-associated secretory phenotype (SASP). However, the mechanisms involved in the conversion of damaged cells into senescent cells remain incompletely understood. Here, we report that multiple types of fibrotic diseases in mice and humans are characterized by the accumulation of iron. We show that vascular and hemolytic injuries, through the release of iron, are efficient in triggering senescence and fibrosis. Interestingly, the accumulation of iron is an intrinsic property of senescent cells that does not require an abnormal surge in extracellular iron. Upon damage, cells initiate an iron accumulation response with abundant ferritin-bound iron within lysosomes and high levels of labile iron, the latter being a main driver of senescence-associated ROS and SASP. Finally, we demonstrate that detection of iron by magnetic resonance imaging (MRI) is a powerful non-invasive method to assess fibrotic burden in the kidneys of mice and patients with renal fibrosis. Our findings establish a central role for iron accumulation in senescence and fibrogenesis.

physiology↗