Biology subjects

Mohl, G. A.

Publications and source records attributed to Mohl, G. A..

3 recordsLinked to original sources

bioRxiv2026

Synaptic activity controls local exposure of an 'eat-me' signal via ANO3-ITPR1 signaling

Neuronal synapses are eliminated during brain development and disease through pruning by glial cells. Individual synapses are marked for engulfment by eat-me signals, which include externalized phosphatidylserine. In apoptotic cells, phosphatidylserine externalization is driven by caspase-dependent activation of Xkr scramblases1 and inactivation of specific flippases2. Localized caspase activation at neuronal synapses can mediate spatially-restricted synaptic phosphatidylserine exposure leading to synapse pruning by glial cells during development and neurodegeneration3-6. It is unknown which caspase-regulated flippases and scramblases promote synaptic phosphatidylserine exposure and whether there are any caspase-independent mechanisms of phosphatidylserine exposure relevant for synapse elimination. To address this question, we here develop a scalable CRISPR screening approach, COMPASS-seq (compartment-anchored sgRNA screen sequencing), to uncover the genetic underpinnings of subcellular phenotypes. COMPASS-seq is compatible with in vitro and in vivo systems and a wide range of subcellular compartments; we here apply it to the neuronal synapse. We discover that inhibition of the caspase-independent, calcium-activated anoctamin ANO3 (TMEM16C) is sufficient to increase synapse numbers in vivo. ANO3 co-localizes with IP3 receptor 1 (ITPR1), a calcium channel in the endoplasmic reticulum, to form a postsynaptic signaling platform that drives spatially restricted phosphatidylserine exposure at synapses. Activation of the ITPR1 calcium channel activity is sufficient to drive synaptic phosphatidylserine exposure via an ANO3-dependent but caspase-independent mechanism. Our results suggest a mechanism for integrating synaptic activity information to control synaptic pruning. The role of ANO3 in regulating synapses could shed light on the mechanisms underlying its numerous associations with both dementia7 and other neurological diseases8,9.

neuroscience↗

bioRxiv2025

PCSK9 and High-Fat Diet Synergistically Induce Neurovascular Dysfunction and Neuroinflammation

Cerebral small vessel disease (CSVD) is strongly linked to metabolic risk factors and represents a major cause of vascular cognitive impairment and dementia. The interactions of genetic and environmental risk factors driving cerebrovascular pathology in metabolic syndrome are poorly understood. Here, we characterize neuroinflammatory and neurodegenerative phenotypes in a mouse model of metabolic syndrome with atherosclerosis induced by hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) overexpression combined with high-fat diet (HFD). PCSK9+HFD mice exhibit hallmark features of CSVD including vascular rarefaction, impaired neurovascular coupling, blood-brain barrier disruption, white matter injury, neuronal loss, and cognitive deficits. Notably, we identify lipid-droplet accumulating microglia (LDAM) as a distinct cellular phenotype that emerges in response to metabolic stress and correlates with cerebrovascular dysfunction. Three-dimensional light sheet microscopy reveals widespread vascular network disruption. Immunophenotyping demonstrates that microglia in PCSK9+HFD group exhibit enhanced phagocytic activation and ramification complexity yet accumulate perivascular amyloid-{beta}, suggesting impaired clearance capacity. Importantly, we observed vascular amyloid-{beta} deposition in wild-type mice without genetic Alzheimers disease mutations, suggesting that metabolic stress contributes to cerebrovascular amyloid pathology. PCSK9+HFD mice displayed recognition memory deficits and increased anxiety-like behavior. Our findings establish that severe hypercholesterolemia accelerates CSVD pathogenesis, and identify LDAM as a distinct pathological feature linking systemic metabolic syndrome to cerebrovascular dysfunction and cognitive impairment.

neuroscience↗

bioRxiv2024

The disease-causing tau V337M mutation induces tau hypophosphorylation and perturbs axon morphology pathways

Tau aggregation is a hallmark of several neurodegenerative diseases, including Alzheimers disease and frontotemporal dementia. There are disease-causing variants of the tau-encoding gene, MAPT, and the presence of tau aggregates is highly correlated with disease progression. However, the molecular mechanisms linking pathological tau to neuronal dysfunction are not well understood. This is in part due to an incomplete understanding of the normal functions of tau in development and aging, and how the associated molecular and cellular processes change in the context of causal disease variants of tau. To address these questions in an unbiased manner, we conducted multi-omic characterization of iPSC-derived neurons harboring the MAPT V337M mutation or MAPT knockdown. RNA-seq, ATAC-seq, and phosphoproteomics revealed that both V337M mutation and tau knockdown perturbed levels of transcripts and phosphorylation of proteins related to axonogenesis or axon morphology. When we directly measured axonogenesis, we found that both MAPT V337M and MAPT knockdown caused decreased axon length. Surprisingly, we found that neurons with V337M tau had much lower tau phosphorylation than neurons with WT tau. CRISPR-based screens uncovered regulators of tau phosphorylation in neurons and found that factors involved in axonogenesis modified tau phosphorylation in both MAPT WT and MAPT V337M neurons. Intriguingly, the p38 MAPK pathway specifically modified tau phosphorylation in MAPT V337M neurons. We propose that V337M tau perturbs tau phosphorylation and axon morphology pathways that are relevant to the normal function of tau in development, which could contribute to previously reported cognitive changes in preclinical MAPT variant carriers.

neuroscience↗