[F31] Spatiotemporal analysis and therapeutic manipulation of motor neuron and lysosomal sterols in FUS-ALS

Description

PROJECT SUMMARY Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a lifetime risk of ~1 in 400 and median survival of only 2-3 years after diagnosis. FUS-ALS, an early-onset, highly aggressive form caused by mutations in the RNA-binding protein Fused in Sarcoma (FUS), is particularly devastating and currently lacks effective therapies. Most work in FUS-ALS has focused on nuclear–cytoplasmic mislocalization and aggregation of FUS, yet the downstream metabolic drivers that actually kill motor neurons remain poorly defined. Recent studies in ALS and related disorders implicate dysregulated sterol metabolism and lysosomal dysfunction as convergent features of neurodegeneration, but the causal relationships among sterol accumulation, lysosomal failure, and motor neuron loss in FUS-ALS have not been established. Preliminary spatial mass spectrometry imaging in a Drosophila melanogaster FUS-ALS model has revealed a striking 2.6- to 7.4-fold accumulation of multiple free sterols specifically in motor neuron somata during symptomatic stages, mirroring sterol pathologies in lysosomal storage diseases. Complementary pilot work in FUS.P525L human iPSC-derived motor neurons shows selective vulnerability to cholesterol-induced lysosomal deacidification. These findings motivate the central hypothesis that free sterol accumulation in motor neurons drives lysosomal deacidification and neurodegeneration in FUS-ALS, and that targeting sterol handling can restore lysosomal function and neuronal viability. Aim 1 will define the pathogenic role of motor neuron sterol accumulation in FUS-ALS by combining longitudinal high-resolution mass spectrometry imaging in Drosophila, dietary sterol manipulation, and lipidomic profiling of cerebrospinal fluid and plasma from clinically characterized FUS-ALS patients. Aim 2 will determine whether sterol accumulation causes lysosomal failure and can be reversed therapeutically by profiling the lysosomal lipidome and acidity in motor neurons, genetically enhancing sterol export via the NPC1a transporter in flies, and testing FDA-approved lysosomal storage disease drugs in FUS.P525L iPSC-derived motor neurons. If successful, this work will validate the lipid-lysosome axis as a novel, druggable pathway in FUS-ALS and establish free sterols as candidate biomarkers for disease staging and therapeutic monitoring. Importantly, the fellowship will provide the candidate with rigorous interdisciplinary training in Drosophila disease modeling, human iPSC-derived motor neuron systems, advanced lipidomics, and computational analysis, in a collaborative environment spanning basic neuroscience, metabolomics, and clinical neurology. This integrated research and training plan is designed to prepare the candidate for a competitive postdoctoral position and, ultimately, for an independent research career leading a laboratory focused on metabolic mechanisms and therapeutic targets in neurodegenerative disease. Istituzione: UNIVERSITY OF PENNSYLVANIA PI: TRISTAN COLMAN O'HARROW Progetto: 1F31NS151580-01

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Source: reporter.nih.gov