| Autor: |
Phillips CL; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill., Faridounnia M; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill., Battaglia RA; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill., Evangelista BA; Department of Neurology, University of North Carolina at Chapel Hill., Cohen TJ; Department of Neurology, University of North Carolina at Chapel Hill., Opal P; Departments of Neurology and Cell and Developmental Biology, Northwestern University, Chicago, IL., Bouldin TW; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill., Armao D; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill.; Department of Radiology, University of North Carolina at Chapel Hill., Snider NT; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill. |
| Abstrakt: |
Giant Axonal Neuropathy (GAN) is a neurodegenerative disease caused by loss-of-function mutations in the KLHL16 gene, encoding the cytoskeleton regulator gigaxonin. In the absence of functional gigaxonin, intermediate filament (IF) proteins accumulate in neurons and other cell types due to impaired turnover and transport. GAN neurons exhibit distended, swollen axons and distal axonal degeneration, but the mechanisms behind this selective neuronal vulnerability are unknown. Our objective was to identify novel gigaxonin interactors pertinent to GAN neurons. Unbiased proteomics revealed a statistically significant predominance of RNA-binding proteins (RBPs) within the soluble gigaxonin interactome and among differentially-expressed proteins in iPSC-neuron progenitors from a patient with classic GAN. Among the identified RBPs was TAR DNA-binding protein 43 (TDP-43), which associated with the gigaxonin protein and its mRNA transcript. TDP-43 co-localized within large axonal neurofilament IFs aggregates in iPSC-motor neurons derived from a GAN patient with the 'axonal CMT-plus' disease phenotype. Our results implicate RBP dysfunction as a potential underappreciated contributor to GAN-related neurodegeneration. |
