Biology subjects

Morella, I.

Publications and source records attributed to Morella, I..

5 recordsLinked to original sources

bioRxiv2026

p70 ribosomal protein S6 Kinase (p70S6K) as a potential peripheral biomarker for mental symptoms in 16p11.2 deletion and duplication syndromes

Neurodevelopmental disorders (NDDs) encompass heterogeneous cognitive, motor, and psychiatric manifestations that typically require extensive behavioural assessments for characterization. Individuals carrying 16p11.2 copy number variations (CNVs), including both deletions and duplications, represent a relatively common NDD subgroup marked by wide variability in psychiatric symptoms, as well as metabolic and peripheral abnormalities, complicating prediction of disease trajectory and treatment response. The identification of biomarkers in easily accessible tissues, such as peripheral blood mononuclear cells (PBMCs), could provide valuable tools for diagnosis and prognosis, yet remains an unmet clinical need. Converging evidence implicates dysregulation of ubiquitous signalling pathways, including ERK and mTOR cascades, in altered protein synthesis across both idiopathic and genetic NDDs. Here, using a hypothesis-driven screening approach, we examined candidate peripheral biomarkers in individuals with 16p11.2 deletions and duplications. We identified a significant reduction of ribosomal protein S6 kinase (p70S6K) levels in PBMCs across both genotypes. Notably, the magnitude of p70S6K reduction correlated with the severity of autistic symptoms independently of CNV genotype. In parallel, MAPK3/ERK1 protein levels mirrored gene dosage, showing increased expression in duplication carriers and reduced levels in deletion carriers, in accordance with the genotype. Collectively, these findings indicate that peripheral molecular alterations may support clinical stratification and suggest that p70S6K represents a promising biomarker for symptom severity and potentially treatment responsiveness in NDD patients carrying 16p11.2 CNVs.

neuroscience↗

bioRxiv2025

Direct pathway bias and altered striatal neurogenesis in human iPSC models of 16p11.2 CNVs: Evidence from single-cell and functional analyses

Striatal medium spiny neurons (MSNs) control motor, cognitive, and social domains via direct (dMSNs) and indirect (iMSNs) basal ganglia pathways. Recent genomic analyses implicate striatal circuit dysfunction in neurodevelopmental disorders (NDDs) and highlight MSNs as a newly recognised cell type affected in schizophrenia, yet much NDD research still focuses on cortical interneurons and glutamatergic neurons, leaving MSN involvement understudied. Here, we use human iPSC-derived MSNs to demonstrate high-fidelity striatal development and explore 16p11.2 copy number variants (CNVs) - mutations predisposing carriers to autism spectrum disorder, schizophrenia, intellectual disability and other NDD conditions featuring basal ganglia deficits. By profiling both 16p11.2 duplication and deletion MSNs, we uncover reciprocal changes in MSN neurogenesis kinetics that converge on a dMSN fate bias. These shifts correspond to altered calcium signalling and enhanced firing upon direct-pathway activation. Our findings reveal a previously unappreciated role for MSN subtype imbalances in NDD pathogenesis and open new avenues for therapeutic intervention.

neuroscience↗

bioRxiv2024

Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain

Mutations in LRRK2 and PINK1 are associated with familial Parkinsons disease (PD). LRRK2 phosphorylates Rab GTPases within the Switch II domain whilst PINK1 directly phosphorylates Parkin and ubiquitin and indirectly induces phosphorylation of a subset of Rab GTPases. Herein we have crossed LRRK2 [R1441C] mutant knock-in mice with PINK1 knock-out (KO) mice and report that loss of PINK1 does not impact endogenous LRRK2-mediated Rab phosphorylation nor do we see significant effect of mutant LRRK2 on PINK1-mediated Rab and ubiquitin phosphorylation. In addition, we observe that a pool of the Rab-specific, PPM1H phosphatase, is transcriptionally up-regulated and recruited to damaged mitochondria, independent of PINK1 or LRRK2 activity. Parallel signalling of LRRK2 and PINK1 pathways is supported by assessment of motor behavioural studies that show no evidence of genetic interaction in crossed mouse lines. Previously we showed loss of cilia in LRRK2 R1441C mice and herein we show that PINK1 KO mice exhibit a ciliogenesis defect in striatal cholinergic interneurons and astrocytes that interferes with Hedgehog induction of glial derived-neurotrophic factor (GDNF) transcription. This is not exacerbated in double mutant LRRK2 and PINK1 mice. Overall, our analysis indicates that LRRK2 activation and/or loss of PINK1 function along parallel pathways to impair ciliogenesis, suggesting a convergent mechanism towards PD. Our data suggests that reversal of defects downstream of ciliogenesis offers a common therapeutic strategy for LRRK2 or PINK1 PD patients whereas LRRK2 inhibitors that are currently in clinical trials are unlikely to benefit PINK1 PD patients.

biochemistry↗

bioRxiv2022

Dissecting the autism-associated 16p11.2 locus identifies multiple drivers in brain phenotypes and unveils a new role for the major vault protein

Using mouse genetic studies, we set out to identify which of the 30 genes causes brain size and other NeuroAnatomical Phenotypes (NAPs) at the autism-associated 16p11.2 locus. We show that multiple genes mapping to this region interact to regulate brain size in contrast to previous studies, with female significantly less affected. Major Vault Protein (MVP), the main component of the vault organelle, is a highly conserved protein found in higher and lower eukaryotic cells, yet its function is not understood. Here we find MVP expression highly specific to the limbic system and Mvp as the top driver gene of NAPs, regulating the morphology of neurons, postnatally and specifically in male. Finally, we demonstrate that the double hemideletion Mvp::Mapk3 rescues NAPs, increases phosphorylation of ERK and alters behavioral performances, suggesting that MVP and ERK share the same signalling pathway, in vivo. Our results highlight that sex-specific cellular and neuroanatomical mechanisms must be considered in neurological disorders such as autism. Most importantly, it provides the first evidence for the involvement of the vault organelle in the regulation of the mammalian brain size and limbic structures.

genetics↗

bioRxiv2018

Modulation of ERK1/MAPK3 potentiates ERK nuclear signalling, facilitates neuronal cell survival and improves memory in mouse models of neurodegenerative disorders

Cell signalling mechanisms are central to neuronal activity and their dysregulation may lead to neurodegenerative processes and associated cognitive decline. So far, a major effort has been directed toward the dissection of disease specific pathways with the still unmet promise to develop precision medicine strategies. With a different approach, here we show that a selective genetic potentiation of neuronal ERK signalling prevents cell death in vitro and in vivo in the mouse brain while ERK attenuation does the opposite. This neuroprotective effect can also be induced pharmacologically by a cell permeable peptide mimicking the loss of ERK1 MAP kinase, leading to a selective enhancement of ERK2 mediated nuclear cell signalling. The drug treatment prevents neurodegeneration in mouse models of Huntingtons (HD), Alzheimers (AD), and Parkinsons disease (PD). Importantly, the selective potentiation of ERK2 signalling facilitates both structural and synaptic plasticity, enhances cognition in healthy mice and rescues mild cognitive impairments in both models of AD and HD. Altogether, our observation truly represents a remarkable example of a shared molecular mechanism across multiple neurodegenerative disorders and a potentially valuable therapeutic target for neuro-enhancement.

neuroscience↗