Biology subjects

Patgiri, A.

Publications and source records attributed to Patgiri, A..

4 recordsLinked to original sources

bioRxiv2025

Brain Mecp2 Gene Dosage and Gene Therapy Shape Multi-Omic Signatures and Biomarkers in Rett Syndrome

Rett syndrome (RTT) is a neurodevelopmental disorder caused by MECP2 mutations. Like other genetic neurodevelopmental disorders, it lacks protein biomarkers to evaluate disease and therapeutic outcomes. We present a strategy to define putative biomarkers of MeCP2 dysfunction in brain with potential to delineate mechanisms and monitor therapeutic interventions. This strategy relies on a library of proteins responsive to Mecp2 gene dosage and correlated with molecular and clinical outcomes after AAV9-mediated MECP2 gene therapy in Mecp2-KO mice. Gene rescue restored MeCP2 in brain, improved clinical phenotypes, and reverted transcriptome and proteome abnormalities. We identified 327 shared proteins among 1852 cortical and hippocampal proteins responsive to Mecp2/MECP2. Of these, 119 also displayed Mecp2/MECP2-dependent transcript changes. Both the Mecp2-responsive proteome and transcript-protein pairs were enriched in synaptic and metabolic pathways, including central carbon and NAD+ metabolism. We used this therapy-responsive protein library to guide selection of candidate cerebrospinal fluid (CSF) biomarkers in RTT. CSF composition from neurotypical and RTT groups was analyzed using ultrasensitive nucleic acid-based multiplexed ELISA. Twenty-eight proteins were altered in RTT, nine overlapping with Mecp2 dosage- and therapy-sensitive proteins. Multivariate regression linked several candidates to Mecp2/MeCP2 abundance and phenotypic improvement in mice. This paradigm provides a rigorous molecular systems-level framework integrating genetics, preclinical gene therapy, and clinical metrics to define robust cross-species putative biomarkers and possible mechanisms in RTT, with potential applicability to other neurodevelopmental disorders. One Sentence SummaryGenetic Identification of cross-species biomarkers and mechanisms in Rett Syndrome

neuroscience↗

bioRxiv2025

Developmental prosopagnosics have normal spatial integration in posterior ventral face-selective regions

Population receptive field (pRF) mapping is an influential neuroimaging technique used to estimate the region of visual space modulating the response of a neuronal population. While pRF mapping has advanced our understanding of visual cortical organization, evidence linking variation in pRF properties to behavioral performance remains limited. One of the most compelling pRF-to-behavior relationships has emerged from research into developmental prosopagnosia (DP). Individuals with DP have severe deficits in facial identity recognition sometimes linked to diminished holistic processing of faces. This perceptual deficit could be explained at the neural level by abnormally small pRFs in face-selective regions that restrict spatial integration of the face information. This hypothesis is supported by data from a small group of DPs but needs to be rigorously evaluated in a larger sample. Here, we measured pRF properties in 20 individuals with DP and 20 controls using a stimulus designed to robustly activate both low- and high-level visual areas. Consistent with previous studies, DPs exhibited weaker face selectivity in core ventral face-selective areas. Crucially, however, across the visual processing hierarchy - from early visual cortex, to intermediate visual areas, and face-selective areas - DPs and controls exhibited remarkable similarity in pRF properties, including pRF size, visual field coverage, and the distribution of pRF centers. Using a larger sample and the latest methods for mapping and modeling pRFs, these results challenge theories attributing DP to reduced spatial integration in face-selective regions. This underscores the need to explore alternative neural mechanisms of DP and to re-evaluate links between pRF properties and behavior more broadly.

neuroscience↗

bioRxiv2024

Adaptive protein synthesis in genetic models of copper deficiency and childhood neurodegeneration

Rare inherited diseases caused by mutations in the copper transporters SLC31A1 (CTR1) or ATP7A induce copper deficiency in the brain, causing seizures and neurodegeneration in infancy through poorly understood mechanisms. Here, we used multiple model systems to characterize the molecular mechanisms by which neuronal cells respond to copper deficiency. Targeted deletion of CTR1 in neuroblastoma cells produced copper deficiency that was associated with a metabolic shift favoring glycolysis over oxidative phosphorylation. Proteomic and transcriptomic analysis of CTR1 KO cells revealed simultaneous upregulation of mTORC1 and S6K signaling and reduced PERK signaling. Patterns of gene and protein expression and pharmacogenomics show increased activation of the mTORC1-S6K pathway as a pro-survival mechanism, ultimately resulting in increased protein synthesis. Spatial transcriptomic profiling of Atp7aflx/Y :: Vil1Cre/+ mice identified upregulated protein synthesis machinery and mTORC1-S6K pathway genes in copper-deficient Purkinje neurons in the cerebellum. Genetic epistasis experiments in Drosophila demonstrated that copper deficiency dendritic phenotypes in class IV neurons are partially rescued by increased S6k expression or 4E-BP1 (Thor) RNAi, while epidermis phenotypes are exacerbated by Akt, S6k, or raptor RNAi. Overall, we demonstrate that increased mTORC1-S6K pathway activation and protein synthesis is an adaptive mechanism by which neuronal cells respond to copper deficiency. SignificanceO_LICopper deficiency is present in rare conditions such as Menkes disease and CTR1 deficiency and in more common diseases like Alzheimers. The mechanisms of resilience and ultimate susceptibility to copper deficiency and associated pathology in the brain remain unknown. C_LIO_LIWe demonstrate that in a human cell line, Drosophila, and the mouse cerebellum, copper-deficient neuronal cells exhibit increased protein synthesis through mTORC1 activation and decreased PERK (EIF2AK3) activity. C_LIO_LIUpregulation of protein synthesis facilitates resilience of neuronal cells to copper deficiency, including partial restoration of dendritic arborization. Our findings offer a new framework for understanding copper deficiency-related pathology in neurological disorders. C_LI

neuroscience↗

bioRxiv2023

Systemic Metabolic and Mitochondrial Defects in Rett Syndrome Models

Genes mutated in monogenic neurodevelopmental disorders are broadly expressed. This observation supports the concept that monogenic neurodevelopmental disorders are systemic diseases that profoundly impact neurodevelopment. We tested the systemic disease model focusing on Rett syndrome, which is caused by mutations in MECP2. Transcriptomes and proteomes of organs and brain regions from Mecp2-null mice as well as diverse MECP2-null male and female human cells were assessed. Widespread changes in the steady-state transcriptome and proteome were identified in brain regions and organs of presymptomatic Mecp2-null male mice as well as mutant human cell lines. The extent of these transcriptome and proteome modifications was similar in cortex, liver, kidney, and skeletal muscle and more pronounced than in the hippocampus and striatum. In particular, Mecp2- and MECP2-sensitive proteomes were enriched in synaptic and metabolic annotated gene products, the latter encompassing lipid metabolism and mitochondrial pathways. MECP2 mutations altered pyruvate-dependent mitochondrial respiration while maintaining the capacity to use glutamine as a mitochondrial carbon source. We conclude that mutations in Mecp2/MECP2 perturb lipid and mitochondrial metabolism systemically limiting cellular flexibility to utilize mitochondrial fuels.

neuroscience↗