Biology subjects

Catinozzi, M.

Publications and source records attributed to Catinozzi, M..

4 recordsLinked to original sources

bioRxiv2024

FUS controls muscle differentiation and structure through LLPS mediated recruitment of MEF2 and ETV5

FUS is an RNA binding protein mutated in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive muscle weakness. We show that ALS-associated FUS mutations lead to ultrastructural defects in muscle of FUS-ALS patients, with disruption of sarcomeres and mitochondria. Studies in mouse and Drosophila models demonstrate an evolutionary-conserved cell autonomous function of FUS in muscle development. Mechanistically, FUS is required for transcription of MEF2 dependent genes, binds to the promoter of genes bound by ETS transcription factors in particular ETV5 and co-activates transcription of MEF2 dependent genes with ETV5. FUS phase separates with ETV5 and MEF2A, and MEF2A binding to FUS is potentiated by ETV5. Last, Etv5 haploinsufficiency exacerbates muscle weakness in a mouse model of FUS-ALS. These findings establish FUS as an essential protein for skeletal muscle structure through its phase separation-dependent recruitment of ETV5 and MEF2, defining a novel pathway compromised in FUS-ALS.

neuroscience↗

bioRxiv2023

DJ-1 products glycolic acid and D-lactate restore deficient axonal trafficking and DNA damage response in FUS and SOD1-associated amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease leading to death within 2-5 years. Currently available drugs can only slightly prolong survival. Despite the progress that has been achieved in unravelling the molecular mechanisms of the disease so far, the underlying pathophysiology is not fully understood. We present novel insights into the pathophysiology of Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (FUS)-ALS by revealing a putatively central role of the Parkinsons disease (PD) associated glyoxylase DJ-1 and its products glycolic acid (GA) and D-lactic acid (DL). Combined, but not single, treatment with GA and DL restored axonal trafficking deficits of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was accompanied by restoration of mitochondrial membrane potential as well as mitochondrial fragmentation (FUS-ALS) or elongation (SOD1-ALS). Furthermore, GA and DL restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites. We further show that despite presenting an early axonal transport deficiency as well, TDP-43 patient-derived MNs did not share this mechanism. While this points towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different gene variants of ALS. Thus, we introduce a putative novel treatment for ALS based on a combination of the two substances GA and DL which might be not only an interesting novel drug candidate in subsets of ALS cases but also in other neurodegenerative diseases characterized by mitochondrial depolarization.

neuroscience↗

bioRxiv2022

Intellectual disability-associated disruption of O-GlcNAcylation impairs neuronal development and cognitive function in Drosophila

O-GlcNAcylation is a reversible co-/post-translational modification involved in a multitude of cellular processes. The addition and removal of O-GlcNAc modification is controlled by two conserved enzymes, O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (OGA). Mutations in OGT have recently been discovered to cause a novel Congenital Disorder of Glycosylation (OGT-CDG) that is characterized by intellectual disability. The mechanisms by which OGT-CDG mutations affect cognition remain unclear. We manipulated O-GlcNAc transferase and O-GlcNAc hydrolase activity in Drosophila and demonstrate an important role of O-GlcNAcylation in habituation learning and synaptic development at the larval neuromuscular junction. Introduction of patient-specific missense mutations into Drosophila O-GlcNAc transferase using CRISPR/Cas9 gene editing, leads to deficits in locomotor function and habituation learning. The habituation deficit can be corrected by blocking O-GlcNAc hydrolysis, indicating that OGT-CDG mutations affect cognitive function via reduced protein O-GlcNAcylation. This study establishes a critical role for O-GlcNAc cycling and disrupted O-GlcNAc transferase activity in cognitive dysfunction. These findings suggest that blocking O-GlcNAc hydrolysis is a potential treatment strategy for OGT-CDG. Author summaryAttachment of single N-acetylglucosamine (GlcNAc) sugars to intracellular proteins has recently been linked to neurodevelopment and cognition. This link has been strengthened by discovery of O-GlcNAc transferase (OGT) missense mutations in intellectual disability. Most of these mutations lie outside the catalytic O-GlcNAc transferase domain and it is unclear how they affect cognitive function. Using the fruit fly Drosophila melanogaster as a model organism, we found that a balance in O-GlcNAc cycling is required for learning and neuronal development. Habituation, a fundamental form of learning, is affected in flies that carry patient-specific OGT mutations, and increasing O-GlcNAcylation genetically corrects the habituation deficit. Our work establishes a critical role for O-GlcNAc cycling in a cognition-relevant process, identifies defective O-GlcNAc transferase activity as a cause of intellectual disability, and proposes underlying mechanisms that can be further explored as treatment targets.

genetics↗

bioRxiv2020

The Drosophila FUS ortholog cabeza promotes adult founder myoblast selection by Xrp1-dependent regulation of FGF signaling

The number of adult myofibers in Drosophila is determined by the number of founder myoblasts selected from a myoblast pool, a process governed by fibroblast growth factor (FGF) signaling. Here, we show that loss of cabeza (caz) function results in a reduced number of adult founder myoblasts, leading to a reduced number and misorientation of adult dorsal abdominal muscles. Genetic experiments revealed that loss of caz function in both adult myoblasts and neurons contributes to caz mutant muscle phenotypes. Selective overexpression of the FGF receptor Htl or the FGF receptor-specific signaling molecule Stumps in adult myoblasts partially rescued caz mutant muscle phenotypes, and Stumps levels were reduced in caz mutant founder myoblasts, indicating FGF pathway deregulation. In both adult myoblasts and neurons, caz mutant muscle phenotypes were mediated by increased expression levels of Xrp1, a DNA-binding protein involved in gene expression regulation. Xrp1-induced phenotypes were dependent on the DNA-binding capacity of its AT-hook motif, and increased Xrp1 levels in founder myoblasts reduced Stumps expression. Thus, control of Xrp1 expression by Caz is required for regulation of Stumps expression in founder myoblasts, resulting in correct founder myoblast selection. Author SummarySkeletal muscles mediate movement, and therefore, proper structure and function of skeletal muscles is required for respiration, locomotion, and posture. Adult muscles arise from fusion of muscle precursor cells during development. In the fruit fly Drosophila melanogaster, muscle precursor cells come in two flavors: founder cells and fusion-competent cells. The number of founder cells selected during development corresponds to the number of adult muscles formed. Here, we report that inactivation of the Drosophila caz gene results in muscle developmental defects. Loss of caz function in both muscle precursor cells and the nerve cells that innervate muscles contributes to the muscle developmental defect. At the molecular level, loss of caz function leads to increased levels of Xrp1. Xrp1 regulates the expression of many other genes, including genes that produce components of the FGF signaling pathway, which is known to be involved in founder cell selection. In all, we uncovered a novel molecular mechanism that regulates founder cell selection during muscle development.

developmental biology↗