Biology subjects

Ros, J.

Publications and source records attributed to Ros, J..

6 recordsLinked to original sources

bioRxiv2026

Glial-specific mitochondrial failure and redox imbalance drive regional vulnerability in Friedreich ataxia

Friedreichs ataxia (FA) is a rare autosomal recessive neurodegenerative disorder caused by reduced expression of frataxin, a mitochondrial protein important for iron-sulfur cluster assembly and mitochondrial homeostasis. Although FA has traditionally been attributed to neuronal dysfunction, increasing evidence suggests that glial cells play a critical role in disease progression, although their contribution remains poorly defined. Using the FXNI151F mouse model, we investigated cell-type-specific metabolic and redox alterations in neurons and glial populations from the cerebrum, cerebellum, and dorsal root ganglia (DRG). Neuronal and glial-enriched fractions were isolated by immunomagnetic separation and analyzed for mitochondrial function, iron metabolism and reactive oxygen species (ROS). The analyses identified the DRG as the most severely affected region, exhibiting early and pronounced mitochondrial respiratory deficits, increased ROS, mitochondrial iron accumulation, lipid peroxidation, and reduced levels of glutathione peroxidase 4 and nuclear factor erythroid 2-related factor 2 in both neuronal and non-neuronal cells. These results highlight the vulnerability of sensory neurons and their supporting satellite glial cells. In contrast, in the cerebrum and cerebellum, astrocytes displayed earlier and more severe alterations than neurons, including impaired respiratory chain efficiency, disrupted complex I-III supercomplex interaction, elevated ROS, and hallmarks of ferroptosis. Neuronal abnormalities emerged later, suggesting that glial dysfunction precedes -or drives- neuronal pathology within the central nervous system. Overall, these findings reveal pronounced region and cell-type-specific vulnerabilities in FA and support the importance of targeting glial mechanisms--particularly iron dysregulation, oxidative stress, and ferroptosis-- as targets for potential therapeutic strategies.

neuroscience↗

bioRxiv2025

Transcriptomic signature reveals sensitivity to tubulin inhibitors in colon cancer

Colon cancer is the second most common cause of cancer death worldwide. Despite advances in the development of new molecular strategies for stratifying patients with colon cancer, many of these patients do not respond adequately to the standard of care. While previous studies have focused on the development of prognostic gene expression signatures, the exploration of predictive signatures to inform treatment decisions remains incomplete. In this study, we leveraged public gene expression datasets to design and experimentally validate a 37-gene expression signature for prognosis in colon cancer patients. We obtained a C-index of 0.732 (0.610-0.853) in four independent studies. Specifically, we discovered that the signature is associated with the mitotic phase of the cell cycle. Furthermore, the signature identified a population of colon cancer patients sensitive to tubulin inhibitor drugs. In particular, we validated in vitro and in vivo the efficacy of paclitaxel, a commonly used tubulin inhibitor in breast cancer treatment, in patient-derived preclinical models. These results highlight the importance of incorporating gene expression signatures to identify new therapeutic options for colon cancer treatment. Furthermore, the identification of alternative treatment options with potentially improved efficacy holds promise for the development of new clinical trials, and reshapes the biomarker-based treatment strategy for second line and refractory colon cancer patients.

cancer biology↗

bioRxiv2024

SYSTEMIC FRATAXIN DEFICIENCY CAUSES TISSUE-DEPENDENT IRON HOMEOSTASIS ALTERATIONS: IMPLICATIONS FOR FRIEDREICH ATAXIA

Friedreich Ataxia (FA) is a cardio-neurodegenerative disease caused by mutations in the frataxin gene, which result in low frataxin expression. It is well-established that frataxin deficiency affects iron homeostasis, but the tissue-specificity of these alterations is poorly understood. In this study, we have analyzed iron homeostasis alterations in the FXNI151F mouse model, which presents systemic frataxin deficiency and neurological defects resembling FA patients. Iron overload is observed in the brain from 21-week old FXNI151F mice, both males and females, and it does not further accumulate in older animals. It is also observed in livers from 39-week old mutant females, but not in males. Iron signaling is altered in all tissues: in brain and liver Iron Regulatory Protein 1 (IRP1) content is decreased, while in heart increased IRP2 and decreased specific aconitase 2 activity are observed. Remarkably, these cardiac alterations are partially restored in 39- week-old animals, suggesting that the heart is activating an iron-deficiency response to compensate for deficient iron-sulfur biogenesis. Our findings demonstrate that frataxin deficiency affects iron homeostasis in a time dependent and tissue-specific manner, and that the pathological mechanisms in FA comprise both iron accumulation and limited iron availability. Understanding this specificity is crucial for the design of iron-related therapeutic interventions aiming to improve FA symptomatology.

biochemistry↗

bioRxiv2024

Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3beta in the impairment of the NRF2 response

Friedreich ataxia (FA) is a rare neurodegenerative disease caused by decreased levels of the mitochondrial protein frataxin. Frataxin has been related in iron homeostasis, energy metabolism, and oxidative stress. Ferroptosis has recently been shown to be involved in FA cellular degeneration; however, its role in dorsal root ganglion (DRG) sensory neurons, the cells that are affected the most and the earliest, is mostly unknown. In this study, we used primary cultures of frataxin-deficient DRG neurons as well as DRG from the FXNI151F mouse model to study ferroptosis and its regulatory pathways. A lack of frataxin induced upregulation of transferrin receptor 1 and decreased ferritin and mitochondrial iron accumulation, a source of oxidative stress. However, there was impaired activation of NRF2, a key transcription factor involved in the antioxidant response pathway. Decreased total and nuclear NRF2 explains the downregulation of both SLC7A11 (a member of the system Xc, which transports cystine required for glutathione synthesis) and glutathione peroxidase 4, responsible for increased lipid peroxidation, the main markers of ferroptosis. Such dysregulation could be due to the increase in KEAP1 and pGSK3{beta} (Tyr216), which promote cytosolic localization and degradation of NRF2. Moreover, there was a deficiency in the LKB1/AMPK pathway, which would also impair NRF2 activity. AMPK acts as a positive regulator of NRF2 and it is activated by the upstream kinase LKB1. The levels of LKB1 were reduced when frataxin decreased, in agreement with reduced pAMPK (Thr172), the active form of AMPK. SIRT1, a known activator of LKB1, was also reduced when frataxin decreased. In conclusion, this study demonstrated that frataxin deficiency in DRG neurons disrupts iron homeostasis and the intricate regulation of molecular pathways affecting NRF2 activation and the cellular response to oxidative stress, leading to ferroptosis.

neuroscience↗

bioRxiv2022

Transcriptomic profiling reveals distinct subsets of immune checkpoint inhibitor-induced myositis

ObjectivesInflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICI) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis. MethodsBulk RNA sequencing was performed on 200 muscle biopsies (35 ICI-myositis, 44 DM, 18 AS, 54 IMNM, 16 IBM, and 33 normal muscle biopsies) and single nuclei RNA sequencing was performed on 22 muscle biopsies (7 ICI-myositis, 4 DM, 3 AS, 6 IMNM, and 2 IBM). ResultsUnsupervised clustering defined three distinct transcriptomic subsets of ICI-myositis: ICI-DM, ICI-MYO1, and ICI-MYO2. ICI-DM included patients with DM and anti-TIF1{gamma} autoantibodies who, like DM patients, overexpressed type 1 interferon-inducible genes. ICI-MYO1 patients had highly inflammatory muscle biopsies and included all patients that developed co-existing myocarditis. ICI-MYO2 was composed of patients with predominant necrotizing pathology and low levels of muscle inflammation. The type 2 interferon pathway was activated both in ICI-DM and ICI-MYO1. Unlike the other types of myositis, all three subsets of ICI-myositis patients overexpressed genes involved in the IL6 pathway. ConclusionsWe identified three distinct types of ICI-myositis based on transcriptomic analyses. The IL6 pathway was overexpressed in all groups, the type I interferon pathway activation was specific for ICI-DM, the type 2 IFN pathway was overexpressed in both ICIDM and ICI-MYO1, and only ICI-MYO1 patients developed myocarditis.

immunology↗

bioRxiv2021

Biochemical alterations precede neurobehavioral deficits in a novel mouse model of Friedreich ataxia

Friedreich Ataxia (FA) is a rare neuro-cardiodegenerative disease, caused by partial deficiency of frataxin, a mitochondrial protein. This deficiency is caused by the presence of a GAA triplet expansion in the first intron of the frataxin gene or, in some patients, by point mutations. Generating mouse models mimicking FA has been challenging, as this disease is manifested when frataxin levels are below a pathological threshold. In the present work, we have characterized a new mouse model of FA (FXNI151F) based on a pathological point mutation (I154F) present in some FA patients. These mice present very low frataxin levels in all tissues and display neurological deficits resembling those observed in FA patients. We have also observed decreased content of components from OXPHOS complexes I and II, decreased aconitase activity, and alterations in the antioxidant defenses. Remarkably, these biochemical alterations precede the appearance of neurological symptoms and present a different profile in heart and brain or cerebellum. The FXNI151F mouse is an excellent tool for analyzing the consequences of frataxin deficiency in different tissues and for testing new therapies.

biochemistry↗