Biology subjects

Prosser, B.

Publications and source records attributed to Prosser, B..

3 recordsLinked to original sources

bioRxiv2026

Pathogenic KIF1A variants differentially disrupt axonal trafficking and impede synaptic development

The nervous system relies on billions of neurons connected through trillions of synapses to support a vast array of vital functions. Despite the critical importance of this synaptic network, the cellular mechanisms dictating synapse formation during human neurodevelopment remain unclear. Long-distance trafficking of synaptic components is critical for both synaptogenesis and the maintenance of synaptic function across lifespan. The microtubule motor KIF1A has a highly conserved role in the trafficking of synaptic vesicle precursors, while mutations in KIF1A are causal for the neurodevelopmental and neurodegenerative disease KIF1A-Associated Neurological Disorder (KAND). Here, we employ isogenic human induced pluripotent stem cells (iPSCs) gene-edited to express pathogenic KIF1A variants to assess how disparate mutations alter synaptic trafficking and function. We compared the effects of both loss-of-function and gain-of-function mutations on KIF1A motor activity. We found that both null (p.C92*) and hypoactive (p.P305L) mutations induce delayed neurite outgrowth, mislocalization of synaptic cargos, and decreased synapse density. Conversely, the hyperactive KIF1A mutation (p.R350G) supports neurite outgrowth but leads to aberrant motility of synaptic vesicle precursors along the axon. Further, live imaging reveals that hyperactive KIF1A induces deficits in the microtubule-dependent patterning of presynaptic components along the developing axon, suggesting a failure to respond to cytoskeletal cues directing cargo delivery. Functional analysis of neuronal activity via multi-electrode arrays reveals delayed synaptic maturation in loss-of-function mutations (p.P305L, p.C92*). In contrast, the hyperactive p.R350G mutation exhibits accelerated activity maturation and possible excitotoxicity. Together, these data provide insights detailing how pathogenic variants in KIF1A causative for KAND exhibit distinct effects at the molecular level that lead to significant downstream deficits in synaptic function in human neurons.

neuroscience↗

bioRxiv2025

ROR2 drives right ventricular heart failure via disruption of proteostasis

BackgroundNo therapies exist to reverse right ventricular failure (RVF), and the molecular mechanisms that drive RVF remain under studied. We recently reported that the developmentally restricted noncanonical WNT receptor ROR2 is upregulated in human RVF in proportion to severity of disease. Here we test the mechanistic role of ROR2 in RVF pathogenesis. MethodsROR2 was overexpressed or knocked down in neonatal rat ventricular myocytes (NRVMs) and then characterized using confocal microscopy, RNAseq, proteomics, proteostatic functional assays, and pacing to assess contractile properties. The impact of cardiac ROR2 expression was evaluated in mice by AAV9-mediated overexpression and by AAV9-mediated delivery of shRNA to knockdown ROR2 in a pulmonary artery banded pressure overload model of RVF. ROR2-modified mice were evaluated by echocardiography, histology, and RV protein synthesis and proteasome capacity. ResultsIn NRVMs, we find that ROR2 profoundly dysregulates the coordination between protein translation and folding. This imbalance leads to excess protein clearance by the ubiquitin proteasome system (UPS) with dramatic impacts on sarcomere and cytoskeletal structure and function. Inhibiting the UPS or restoring chaperone expression is sufficient to partially rescue ROR2-induced structural and contractile deficits in cardiomyocytes. In mice, forced cardiac ROR2 expression is sufficient to disrupt proteostasis and drive RVF, while conversely ROR2 knockdown partially rescues proteostasis and RV structure and function in a pressure overload model of RVF. ConclusionsIn sum, ROR2 is a key driver of RVF pathogenesis through proteostatic disruption and, thus, provides a promising target to treat RVF.

molecular biology↗

bioRxiv2018

Microtubules provide a viscoelastic resistance to myocyte motion.

BackgroundMicrotubules (MT) buckle and bear load during myocyte contraction, a behavior enhanced by post-translational detyrosination. This buckling suggests a spring-like resistance against myocyte shortening, which could store energy and aid myocyte relaxation. Despite this visual suggesting of elastic behavior, the precise mechanical contribution of the cardiac MT network remains to be defined.\n\nMethodsHere we experimentally and computationally probe the mechanical contribution of stable microtubules and their influence on myocyte function. We use multiple approaches to interrogate viscoelasticity and cell shortening in primary murine myocytes where either MTs are depolymerized or detyrosination is suppressed, and use the results to inform a mathematical model of myocyte viscoelasticity.\n\nResultsMT ablation by colchicine concurrently enhances both the degree of shortening and speed of relaxation, a finding inconsistent with simple spring-like microtubule behavior, and suggestive of a viscoelastic mechanism. Axial stretch and transverse indentation confirm that microtubules increase myocyte viscoelasticity. Specifically, increasing the rate of strain amplifies the MT contribution to myocyte stiffness. Suppressing MT detyrosination with parthenolide or via overexpression of tubulin tyrosine ligase (TTL) has mechanical consequences that closely resemble colchicine, suggesting that the mechanical impact of MTs relies on a detyrosination-dependent linkage with the myocyte cytoskeleton. Mathematical modeling affirms that alterations in cell shortening conferred by either MT destabilization or tyrosination can be attributed to internal changes in myocyte viscoelasticity.\n\nConclusionsThe results suggest that the cardiac MT network regulates contractile amplitudes and kinetics by acting as a cytoskeletal shock-absorber, whereby MTs provide breakable cross-links between the sarcomeric and non-sarcomeric cytoskeleton that resist rapid length changes during both shortening and stretch.

biophysics↗