Biology subjects

Starr, L.

Publications and source records attributed to Starr, L..

2 recordsLinked to original sources

bioRxiv2026

Disrupted glial-mediated synaptic refinement in Fragile X syndrome

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism, results from the loss of the RNA-binding protein fragile X mental retardation protein (FMRP). FMRP is a translational regulator and is highly expressed in glial cells, where its role in neural circuit development remains poorly defined. Here, it was observed that Fmr1 knockout mice exhibit reduced synapse size and accelerated eye-specific segregation. To examine which cell-types participate in this process, a multi-omic framework was applied to FXS model mice at postnatal day 7, a critical window for synaptic remodeling in the retinogeniculate pathway, an established model system utilized to study synaptic pruning. Single-cell transcriptomics revealed coordinated alterations in microglia, astrocytes, and neurons in genes linked to synaptic pruning. Computational modeling further demonstrated enhanced astrocyte-to-microglia signaling, particularly through Ephrin A (EphA)- and semaphorin-mediated pathways, while lipidomic profiling revealed reductions in EphA-associated lipid species required for lipid raft stability and receptor localization. Consistent with these observations, a glial engulfment assay indicated that FXS microglia and astroglia over-engulf synaptic material in the lateral geniculate nucleus, supporting the transcriptomic profile. Together, these findings identify impaired glial-driven synaptic refinement as an early mechanistic feature of FXS pathogenesis, highlighting the genes involved in this process as potential therapeutic targets during circuit development.

neuroscience↗

bioRxiv2025

Cell type-specific associations with Alzheimer's Disease conserved across racial and ethnic groups

Genomic studies at single-cell resolution have implicated multiple cell types associated with clinical and pathological traits in Alzheimers Disease (AD), but have not examined common features across broad, multi-ethnic populations, and across multiple regions. To bridge this gap, we performed single-nucleus RNA-seq and ATAC-seq profiling of cortical and subcortical brain regions from post-mortem samples across Non-Latin White, African American, and Latin donors (the latter of any race). Using discrete and continuous dissection of molecular programs, we elucidate cell-type-specific glial and neuronal signatures associated with AD across multiple population groups. Notably, we found that multiple microglial (GPNMB+, CD74+, and CR1+ subgroups) and astrocyte (SERPINH1+ and WIF1+ subgroups) signatures are associated with worse clinical and pathological phenotypes across all three population groups. We also report continuous gene expression factors in oligodendrocytes that are not captured by discrete clusters, yet still show strong associations with disease phenotypes. Finally, we observe these discrete cellular identities and continuous gene programs separate cognitively impaired donors into 6 molecularly distinct subgroups that span racial and ethnic population groups. Overall, our study identifies key cell types and gene programs implicated in AD that are shared across population groups, and provides an initial data set that underscores how representative sampling can capture conserved signatures as well as disease heterogeneity, leading to better prioritization of key cell types for further investigation.

neuroscience↗