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Pathogenic TFG Mutations Underlying Hereditary Spastic Paraplegia Impair Secretory Protein Trafficking and Axon Fasciculation.

Title: Pathogenic TFG Mutations Underlying Hereditary Spastic Paraplegia Impair Secretory Protein Trafficking and Axon Fasciculation.
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Name(s): Slosarek, Erin L, author
Schuh, Amber L, author
Pustova, Iryna, author
Johnson, Adam, author
Bird, Jennifer, author
Johnson, Matthew, author
Frankel, E B, author
Bhattacharya, Nilakshee, author
Hanna, Michael G, author
Burke, Jordan E, author
Ruhl, David A, author
Quinney, Kyle, author
Block, Samuel, author
Peotter, Jennifer L, author
Chapman, Edwin R, author
Sheets, Michael D, author
Butcher, Samuel E, author
Stagg, Scott M, author
Audhya, Anjon, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2018-08-28
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Length-dependent axonopathy of the corticospinal tract causes lower limb spasticity and is characteristic of several neurological disorders, including hereditary spastic paraplegia (HSP) and amyotrophic lateral sclerosis. Mutations in Trk-fused gene (TFG) have been implicated in both diseases, but the pathomechanisms by which these alterations cause neuropathy remain unclear. Here, we biochemically and genetically define the impact of a mutation within the TFG coiled-coil domain, which underlies early-onset forms of HSP. We find that the TFG (p.R106C) mutation alters compaction of TFG ring complexes, which play a critical role in the export of cargoes from the endoplasmic reticulum (ER). Using CRISPR-mediated genome editing, we engineered human stem cells that express the mutant form of TFG at endogenous levels and identified specific defects in secretion from the ER and axon fasciculation following neuronal differentiation. Together, our data highlight a key role for TFG-mediated protein transport in the pathogenesis of HSP.
Identifier: FSU_pmch_30157421 (IID), 10.1016/j.celrep.2018.07.081 (DOI), PMC6152936 (PMCID), 30157421 (RID), 30157421 (EID), S2211-1247(18)31199-9 (PII)
Keywords: COPII, L1CAM, Trk-fused gene, Axon bundling, Early secretory pathway, Hereditary spastic paraplegia, Neurodegeneration, Vesicle trafficking
Grant Number: T32 GM008688, UL1 TR000427, S10 RR027000, P30 CA014520, R35 GM118131, R21 HD076828, R01 GM086892, P41 GM103399, R01 GM110567
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152936.
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_30157421
Host Institution: FSU
Is Part Of: Cell reports.
2211-1247
Issue: iss. 9, vol. 24

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Slosarek, E. L., Schuh, A. L., Pustova, I., Johnson, A., Bird, J., Johnson, M., … Audhya, A. (2018). Pathogenic TFG Mutations Underlying Hereditary Spastic Paraplegia Impair Secretory Protein Trafficking and Axon Fasciculation. Cell Reports. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_30157421