Biology subjects

Ferri, A.

Publications and source records attributed to Ferri, A..

6 recordsLinked to original sources

bioRxiv2026

Nuclear DNA damage is a primary driver of mitochondrial dysfunction in C9ORF72 ALS/FTD

Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration associated with genomic instability and mitochondrial dysfunction, although the mechanistic relationship between these hallmarks remains unclear. To determine whether nuclear DNA damage alone induces mitochondrial dysfunction, we exploited the AID-DIvA system, selectively generating DNA double-strand breaks (DSBs) in nuclear DNA. DSB induction caused early impairment of mitochondrial bioenergetics, including reduced basal respiration, ATP-linked respiration, and maximal respiratory capacity, preceding more pronounced mitochondrial alterations, after prolonged damage. Resolution of DSBs restored mitochondrial function, demonstrating a direct and reversible link between nuclear genome instability and mitochondrial dysfunction. Mechanistically, persistent activation of the DNA damage response (DDR) triggered PARP1-dependent NAD{square} depletion, while PARP1 inhibition rescued mitochondrial respiration and ATP synthesis. We next investigated the consequences of DDR activation triggered by the expression of 102 (G4C2) repeats in an inducible cell model of C9ORF72-linked ALS. In these cells, DDR activation preceded mitochondrial dysfunction, recapitulating the sequence observed in AID-DIvA cells. Mitochondrial defects included impaired oxidative phosphorylation and reduced ATP production without increased mitochondrial ROS, suggesting that DNA damage signalling acts upstream of mitochondrial dysfunction. In support of this hypothesis, inhibition of ATM as well as nicotinamide riboside-mediated replenishment of cellular NAD+significantly restored mitochondrial functions. Collectively, our findings identify nuclear DNA damage as a trigger of mitochondrial dysfunction and uncover a pathogenic DDR-mitochondria crosstalk mediated by persistent DNA damage signalling. These results support a bidirectional relationship between genome instability and mitochondrial dysfunction and highlight mitochondrial and DNA damage response modulators as potential therapeutic targets for ALS and related neurodegenerative disorders.

cell biology↗

bioRxiv2025

Caspase-8 is a novel modulator of Homologous Recombination Repair in response to ionizing radiations

Caspase-8 is a cysteine protease historically regarded as anti-neoplastic protein, thanks to its role in apoptosis. However, Caspase-8 expression is retained or even enhanced in several tumors, including glioblastoma (GBM), where it plays pro-tumor functions. We previously reported that it is a negative prognostic factor and contributes to resistance against DNA damaging agents, such as ionizing radiations (IR) and Temozolomide, commonly used in standard GBM treatment. We therefore investigated whether Caspase-8 may sustain DNA repair pathways proficiency in GBM. Here we uncover a novel role of Caspase-8 as promoter of the Homologous Recombination Repair (HRR). Importantly, IR promote Caspase-8 transient nuclear translocation and its recruitment to the chromatin. Moreover, Caspase-8 sustains the expression and the recruitment to the chromatin upon IR of RAD51 and CtIP, two key players of the HRR. Consistently, we identify a synthetically lethal interaction between Caspase-8 and PARP inhibition, that may ameliorate GBM response to IR. Remarkably, by using Caspase-8-/- murine embryo fibroblasts and a Drosophila melanogaster Caspase-8 mutant, we demonstrate that Caspase-8 plays an evolutionary conserved role in DNA repair. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=149 HEIGHT=200 SRC="FIGDIR/small/656091v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1016001org.highwire.dtl.DTLVardef@145ed73org.highwire.dtl.DTLVardef@1e847d5org.highwire.dtl.DTLVardef@c417e1_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Sex-dimorphic effects of neuromelanin buildup in rodent nigral dopamine neurons: implications for sex-biased vulnerability in Parkinson's disease

Neuromelanin (NM) is a dark pigment accumulating with age in human substantia nigra pars compacta (SNpc) dopamine (DA) neurons, conferring the dark look that inspired nigral areas name. Despite NM has long been associated with Parkinsons disease (PD), as melanized neurons favorably degenerate during disease development, NM functions within SNpc DA neurons are still mostly elusive. Here, by exploiting an NM-producing rat model generated by viral vector-induced expression of human Tyrosinase (hTyr), we inspected NM impact on nigral DA neurons survival and activity, on mitochondrial functionality of SNpc, and behaviors resembling non-motor and motor PD symptoms. Our data reveal sex dimorphism in NM effects on nigrostriatal dopamine circuit, with sex-biased alterations in neuronal firing activity and underlying intrinsic currents, nigral mitochondrial functions, and non-motor PD symptoms (anxiety). In conclusion, this study discloses unrealized NM effects within nigral DA neurons, advancing our comprehension of sex-specific features shaping sex-biased vulnerability to PD.

neuroscience↗

bioRxiv2024

Brown Adipose Tissue undergoes pathological perturbations and shapes C2C12 myoblast homeostasis in the SOD1-G93A mouse model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of motor neurons. While the contribution of peripheral organs remains incompletely understood, recent evidence suggests that brown adipose tissue (BAT) and its secreted extracellular vesicles (EVs) could play a role in diseased context as ALS. In this study, we employed a multi-omics approach, including RNA sequencing (GEO identifier GSE273052) and proteomics (ProteomeXchange identifier PXD054147), to investigate the alterations in BAT and its EVs in the SOD1-G93A mouse model of ALS. Our results revealed significant changes in the proteomic and transcriptomic profiles of BAT from SOD1-G93A mice, highlighting ALS-related features such as mitochondrial dysfunction and impaired differentiation capacity. Specifically, primary brown adipocytes (PBAs) from SOD1-G93A mice exhibited differentiation impairment, respiratory defects, and alterations in mitochondrial dynamics. Furthermore, the BAT-derived EVs from SOD1-G93A mice displayed distinct changes in size distribution and cargo content, which negatively impacted the differentiation and homeostasis of C2C12 murine myoblasts, as well as induced atrophy in C2C12-derived myotubes. These findings suggest that BAT undergoes pathological perturbations in ALS, contributing to skeletal muscle degeneration through the secretion of dysfunctional EVs. This study provides novel insights into the role of BAT in ALS pathogenesis and highlights potential therapeutic targets for mitigating muscle wasting in ALS patients.

neuroscience↗

bioRxiv2021

Targeting SerpinE1 reverses cellular features of Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, fatal disease caused by Lamin A mutation, leading to altered nuclear architecture, loss of perinuclear heterochromatin and deregulated gene expression. HGPS patients eventually die by coronary artery disease and cardiovascular alterations. However, how deregulated transcriptional networks at the cellular level impact on the systemic disease phenotype is currently unclear. We have performed a longitudinal genome-wide analysis of gene expression in primary HGPS fibroblasts from patients at two sequential stages of disease that revealed a progressive activation of Rho signaling and SerpinE1, also known as Plasminogen Activator Inhibitor (PAI-1). siRNA-mediated downregulation or pharmacological inhibition of SerpinE1 by TM5441 could revert key pathological features of HGPS in patient-derived fibroblasts, including re-activation of cell cycle progression, reduced DNA damage signaling, decreased expression of pro-fibrotic genes and recovery of mitochondrial defects. These effects were accompanied by reduced levels of Progerin and correction of nuclear abnormalities. These data point to SerpinE1 as a novel potential effector of HGPS pathogenesis and target for therapeutic interventions.

cell biology↗

bioRxiv2020

Altered skeletal muscle glucose-fatty acid flux in amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons, yet an increasing number of studies in both mouse models and patients with ALS suggest that altered metabolic homeostasis is a feature of disease. Pre-clinical and clinical studies have shown that modulation of energy balance can be beneficial in ALS. However, our capacity to target specific metabolic pathways or mechanisms requires detailed understanding of metabolic dysregulation in ALS. Here, using the SOD1G93A mouse model of ALS, we demonstrate that an increase in whole-body metabolism occurs at a time when glycolytic muscle exhibits an increased dependence on fatty acid oxidation. Using myotubes derived from muscle of ALS patients, we also show that increased dependence on fatty acid oxidation is associated with increased whole-body energy expenditure. In the present study, increased fatty acid oxidation was associated with slower disease progression. However, we observed considerable heterogeneity in whole-body metabolism and fuel oxidation profiles across our patient cohort. Thus, future studies that decipher specific metabolic changes at an individual patient level are essential for the development of treatments that aim to target metabolic pathways in ALS.

neuroscience↗