Biology subjects

Della Valle, I.

Publications and source records attributed to Della Valle, I..

3 recordsLinked to original sources

bioRxiv2024

Cytoplasmic accumulation of a splice variant of hnRNP A2/B1 contributes to FUS-associated toxicity in a mouse model of ALS

Genetic and experimental findings point to a crucial role of RNA dysfunction in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). Evidence suggests that mutations in RBPs such as FUS, a gene associated with ALS, affect the regulation of alternative splicing. We have previously shown that the overexpression of wild-type FUS in mice, a condition that induces ALS-like phenotypes, impacts the splicing of hnRNP A2/B1, a protein with key roles in RNA metabolism, suggesting that a pathological connection between FUS and hnRNP A2/B1 might promote FUS-associated toxicity. Here we report that the expression and distribution of different hnRNP A2/B1 splice variants are modified in the affected tissues of mice overexpressing wild-type FUS. Notably, degenerating motor neurons are characterized by the cytoplasmic accumulation of splice variants of hnRNP A2/B1 lacking exon 9 (hnRNP A2b/B1b). In vitro studies show that exon 9 skipping affects the nucleocytoplasmic distribution of hnRNP A2/B1, promoting its localization into stress granules (SGs), and demonstrate that cytoplasmic localization is the primary driver of hnRNP A2b recruitment into SGs and cell toxicity. Finally, boosting exon 9 skipping using splicing switching oligonucleotides exacerbates disease phenotypes in wild-type FUS mice. Altogether, these findings reveal that alterations of the nucleocytoplasmic distribution of hnRNP A2/B1, driven by FUS-induced splicing changes, likely contribute to motor neuron degeneration in ALS.

neuroscience↗

bioRxiv2024

DNA damage response defects induced by the formation of TDP-43 and mutant FUS cytoplasmic inclusions and their pharmacological rescue.

Formation of cytoplasmic inclusions (CIs) of TDP-43 and FUS, along with DNA damage accumulation, is a hallmark of affected motor neurons in Amyotrophic Lateral Sclerosis (ALS). However, the impact of CIs on DNA damage response (DDR) and repair in this pathology remains unprobed. Here, we show that CIs of TDP-43 and FUSP525L, co-localizing with stress granules, lead to a dysfunctional DDR activation associated with physical DNA breakage. Inhibition of the activity of the DDR kinase ATM, but not of ATR, abolishes DDR signaling, indicating that DNA double-strand breaks (DSBs) are the primary source of DDR activation. In addition, cells with TDP-43 and FUSP525L CIs exhibit reduced DNA damage-induced RNA synthesis at DSBs. We previously showed that the two endoribonucleases DROSHA and DICER, also known to interact with TDP-43 and FUS during small RNA processing, contribute to DDR signaling at DSBs. Treatment with enoxacin, which stimulates DDR and repair by boosting the enzymatic activity of DICER, restores a proficient DDR and reduces DNA damage accumulation in cultured cells with CIs and in vivo in a murine model of ALS. In Drosophila melanogaster, Dicer-2 overexpression rescues TDP-43-mediated retinal degeneration. In summary, our results indicate that the harmful effects caused by TDP-43 and FUS proteinopathies include genotoxic stress and that the pharmacological stimulation of the DNA damage signaling and repair counteracts it.

molecular biology↗

bioRxiv2023

Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia

Immunometabolism investigates the complex interplay between the immune system and cellular metabolism. This study highlights the effects of mitochondrial frataxin (FXN) depletion, which causes Friedreichs ataxia (FRDA), a neurodegenerative condition characterized by coordination and muscle control deficiencies. Using single-cell RNA sequencing, we identified specific cell groups in the cerebellum of a FRDA mouse model, emphasizing a notable inflammatory microglial response. These FXN-deficient microglia cells exhibited enhanced inflammatory reactions. Furthermore, our metabolomic analyses revealed increased glycolysis and itaconate production in these cells, possibly driving the inflammation. Remarkably, butyrate treatment counteracted these immunometabolic changes, triggered an antioxidant response via the itaconate-Nrf2-GSH pathways, and dampened inflammation. The study also pinpointed Hcar2 (GPR109A) as a potential agent for butyrate anti-inflammatory impact on microglia. Tests on FRDA mice highlighted the neuroprotective attributes of butyrate intake, bolstering neuromotor performance. In essence, our findings shed light on how cerebellar microglia activation contributes to FRDA and highlight butyrate potential to alleviate neuroinflammation, rectify metabolic imbalances, and boost neuromotor capabilities in FRDA and similar conditions.

physiology↗