Biology subjects

Gastaldo, D.

Publications and source records attributed to Gastaldo, D..

4 recordsLinked to original sources

bioRxiv2026

Phosphorylated ubiquitin is a secondary messenger and an epigenetic mark mediating mitochondria to nucleus signaling

AbstractParkinsons disease (PD) is commonly associated with dysfunctional mitochondrial homeostasis. PINK1, a S/T kinase mutated in early-onset PD, generates phosphoserine 65 ubiquitin (pS65Ub) on damaged mitochondria facilitating their removal. Here, we show that pS65Ub translocates into the nucleus after generation at damaged mitochondria and is directly attached to substrates by resident E3 ligases. Histone H2A is a major substrate and is modified at lysine 119 (H2AK119) by the polycomb silencer, E3 ligase RING1B. At nucleosomes, pS65Ub simultaneously suppresses RING1B and potentiates H2A deubiquitinases USP16 and USP21. Epigenetic profiling and RNA sequencing reveal that pS65Ub is enriched at the promoters of poorly expressed yet dynamically regulated genes and is associated with H2AK119ub depletion. Functionally, we show that pS65Ub enrichment drives polycomb target gene expression, which accelerates the maturation of dopaminergic neurons. Importantly, post-mortem PD brains exhibit elevated nuclear pS65Ub, potentially linking nuclear pS65Ub accumulation with disease pathogenesis. Together, these data indicate that pS65Ub generated at damaged mitochondria regulates fundamental cellular processes at distant sites.

cell biology↗

bioRxiv2025

Ataxin-2 knockdown is neuroprotective via cell-autonomous and non-cell-autonomous mechanisms

Ataxin-2 (ATXN2) is a genetic modifier of TDP-43 toxicity and a promising therapeutic target in amyotrophic lateral sclerosis (ALS). However, the mechanisms underlying its neuroprotective effects remain poorly understood. Here we show that ataxin-2 reduction confers neuroprotection by engaging adaptive metabolic programs in both neuronal and glial cells. Using global proteomic profiling in yeast and mouse TDP-43 models, we establish that pbp1/ataxin-2 (pbp1 is the yeast ataxin-2 ortholog) activates orthogonal stress-adaptive programs that enable alternative energy production and augment trophic support, rather than simply reversing TDP-43-induced damage. In neurons, ataxin-2 downregulation activates glycolysis and reductive glutamine carboxylation driven by IDH1, restoring ATP production independently of impaired mitochondria. In astrocytes, ataxin-2 downregulation upregulates cholesterol biosynthesis via HMGCS1, enhancing trophic support to neurons in a non-cell-autonomous manner. Full neuroprotection requires both mechanisms: neuronal survival is only completely rescued when ataxin-2 is reduced in the context of neuron-astrocyte co-cultures. Importantly, ataxin-2 downregulation protects against both TDP-43 gain-of-function and loss-of-function toxicity, broadening its therapeutic relevance. Collectively, our findings reveal novel mechanisms by which ataxin-2 orchestrates adaptive metabolic resilience and establish ataxin-2 as a regulator of stress-adaptive response in brain cells under the conditions of stress.

neuroscience↗

bioRxiv2022

Cell type-specific disruption of cortico-striatal circuitry drive repetitive patterns of behaviour in fragile X syndrome model mice

Individuals with fragile X syndrome (FXS) are frequently diagnosed with autism spectrum disorder (ASD), including increased risk for restricted and repetitive behaviours (RRBs). Consistent with observations in humans, FXS model mice display distinct RRBs and hyperactivity that are consistent with dysfunctional cortico-striatal circuits, an area relatively unexplored in FXS. Using a multidisciplinary approach, we dissected the contribution of two populations of striatal medium spiny neurons (SPNs) in the expression of RRBs in FXS model mice. We found that dysregulated protein synthesis at cortico-striatal synapses is a molecular culprit of the synaptic and ASD-associated motor phenotypes displayed by FXS model mice. Cell-type-specific translational profiling of the FXS mouse striatum revealed differentially translated mRNAs, providing critical information concerning potential therapeutic targets. Our findings represent the first evidence of a cell-type specific impact of the loss of FMRP on translation and the sequence of neuronal events in the striatum that drive RRBs in FXS. HighlightsDysregulated striatal protein synthesis underlies altered synaptic plasticity and RRBs displayed by FXS model mice FXS model mice exhibit cell type-specific molecular, morphological, and synaptic changes in the dorsolateral striatum Selective deletion of Fmr1 from dSNPs in mice alters translation and causes repetitive behavior TRAP-Seq indicates that there is altered binding of >120 mRNAs to ribosomes in dSNPs of Fmr1 KO mice G-protein signaling (RGS) 4 translation is significantly reduced in dSPNs in FXS model mice Treatment of FXS model mice with VU0152100, a positive allosteric modulator of the M4 muscarinic receptor that is upstream of RGS4, can reverse RRBs

neuroscience↗

bioRxiv2018

The autism and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity

Copy-number variants of the CYFIP1 gene in humans have been linked to Autism and Schizophrenia, two neuropsychiatric disorders characterized by defects in brain connectivity. CYFIP1 regulates molecular events underlying post-synaptic functions. Here, we show that CYFIP1 plays an important role in brain functional connectivity and callosal functions. In particular, we find that Cyfip1 heterozygous mice have reduced brain functional connectivity and defects in white matter architecture, typically relating to phenotypes found in patients with Autism, Schizophrenia and other neuropsychiatric disorders. In addition, Cyfip1 deficient mice present deficits in the callosal axons, namely reduced myelination, altered pre-synaptic function, and impaired bilateral-connectivity related behavior. Altogether, our results show that Cyfip1 haploinsufficiency compromises brain connectivity and function, which might explain its genetic association to neuropsychiatric disorders.

neuroscience↗