Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure

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Item Type:	Article
Title:	Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure
Creators Name:	Beetz, C., Johnson, A., Schuh, A.L., Thakur, S., Varga, R.E., Fothergill, T., Hertel, N., Bomba-Warczak, E., Thiele, H., Nürnberg, G., Altmüller, J., Saxena, R., Chapman, E.R., Dent, E.W., Nürnberg, P. and Audhya, A.
Abstract:	Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of gait disorders. Their pathological hallmark is a length-dependent distal axonopathy of nerve fibers in the corticospinal tract. Involvement of other neurons can cause additional neurological symptoms, which define a diverse set of complex hereditary spastic paraplegias. We present two siblings who have the unusual combination of early-onset spastic paraplegia, optic atrophy, and neuropathy. Genome-wide SNP-typing, linkage analysis, and exome sequencing revealed a homozygous c.316C>T (p.R106C) variant in the Trk-fused gene (TFG) as the only plausible mutation. Biochemical characterization of the mutant protein demonstrated a defect in its ability to self-assemble into an oligomeric complex, which is critical for normal TFG function. In cell lines, TFG inhibition slows protein secretion from the endoplasmic reticulum (ER) and alters ER morphology, disrupting organization of peripheral ER tubules and causing collapse of the ER network onto the underlying microtubule cytoskeleton. The present study provides a unique link between altered ER architecture and neurodegeneration.
Keywords:	Membrane Trafficking, COPII-Mediated Secretion, ER Exit Site, Animals, Mice, Rats, Zebrafish
Source:	Proceedings of the National Academy of Sciences of the United States of America
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Volume:	110
Number:	13
Page Range:	5091-5096
Date:	26 March 2013
Official Publication:	https://doi.org/10.1073/pnas.1217197110
PubMed:	View item in PubMed

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