Biology subjects

Valente, E. M.

Publications and source records attributed to Valente, E. M..

3 recordsLinked to original sources

bioRxiv2026

Massive-scale single-nucleus multi-omics identifies novel rare noncoding drivers of Parkinson's disease

Most genetic variants contributing to complex diseases reside in the noncoding genome. While common variants uncovered by genome-wide association studies often fail to explain much of the observed heritability of these diseases, rare variants often have higher effect sizes and cumulatively explain a larger portion of heritability. However, rare variants, particularly rare noncoding variants, have remained under-characterized largely due to the difficulties of accurately predicting variant functionality at scale, given that each individual carries an average of [~]10,000 rare variants. Here, we generated multi-omic data from >3.3 million nuclei sampled from five brain regions across a cohort of 80 individuals with Parkinsons disease (PD) and 21 neurologically normal control individuals with matched 30x whole-genome sequencing. We use this data to identify cell type-specific features of PD, map cell type-specific chromatin accessibility and expression quantitative trait loci, and train machine learning models to predict the effect of variants on gene regulation. We identify rare noncoding variants statistically associated with sporadic PD and extend our approaches to predict drivers of familial PD of unknown genetic origin. Our results underscore the significance of rare noncoding variants in complex diseases and provide a roadmap for applying similar approaches in other disease systems.

genetics↗

bioRxiv2025

FGF overactivation underlies reduced neurogenesis in cerebellar organoid models of neurodevelopmental ciliopathy

The primary cilium acts as a specialized signaling compartment that coordinates multiple developmental pathways, yet its role in regulating signaling activity during human brain development remains poorly understood. Biallelic mutations in ciliary genes cause neurodevelopmental ciliopathies such as Joubert syndrome, which are characterized by cerebellar hypoplasia and dysplasia. Here, we generated human cerebellar organoids carrying null or patient-derived mutations in RPGRIP1L, a ciliary transition zone gene associated with Joubert Syndrome, to investigate how ciliary dysfunction alters human cerebellar neurogenesis. While control organoids robustly express markers of cerebellar glutamatergic and GABAergic lineages including Purkinje cells, RPGRIP1L-deficient organoids display a consistent and severe reduction in Purkinje cell markers, accompanied by impaired neurogenesis and increased progenitor proliferation. These defects coincide with prolonged overactivation of the FGF/MAPK signaling pathway. We further show that the MAPK effector pMEK1/2 localizes at the base of primary cilia, where its levels are significantly increased in RPGRIP1L-deficient cerebellar progenitors. Pharmacological inhibition of FGF receptors reduces pMEK1/2 activation at cilia base and rescues both the proliferation-neurogenesis imbalance and Purkinje lineage defects, without restoring the underlying ciliary abnormalities. Together, our findings identify the primary cilium as a compartment that refines FGF/MAPK signaling in human cerebellar progenitors, and support a model in which RPGRIP1L restrains FGF pathway activity to promote neurogenesis. These results provide a mechanism linking ciliary dysfunction to altered cerebellar development and provide new insight into the developmental origin of cerebellar impairment in neurodevelopmental ciliopathies

developmental biology↗

bioRxiv2021

Neuropsychological assessment and virtual reality training of social prediction in patients with cerebellar malformation

It has been proposed that impairments of the predictive function exerted by the cerebellum may account for social cognition deficits. Here, we integrated cerebellar functions in a predictive coding framework to elucidate how cerebellar alterations could affect the predictive processing of others behavior. Experiment 1 demonstrated that cerebellar patients were impaired in relying on contextual information during action prediction, and this impairment was significantly associated with social cognition abilities. Experiment 2 indicated that patients with cerebellar malformation showed a domain-general deficit in using contextual information to predict both social and physical events. Experiment 3 provided first evidence that a social-prediction training in virtual reality could boost the ability to use context-based predictions to understand others intentions. These findings shed new light on the predictive role of the cerebellum and its contribution to social cognition, paving the way for new approaches to the rehabilitation of the Cerebellar Cognitive Affective Syndrome.

neuroscience↗