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

Cell Reports
Erin L SlosarekAnjon Audhya

Abstract

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.

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Citations

May 7, 2019·Traffic·Jennifer PeotterAnjon Audhya
May 21, 2020·Disease Models & Mechanisms·Rebecca YarwoodMartin Lowe
Aug 17, 2021·Frontiers in Molecular Biosciences·Elisabeth LataMartin Teichmann
Oct 20, 2020·ACS Pharmacology & Translational Science·Nihar KinarivalaPaul C Trippier
Nov 16, 2021·Movement Disorders : Official Journal of the Movement Disorder Society·Dallah YooTae-Beom Ahn

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Methods Mentioned

BETA
exome sequencing
circular dichroism
size exclusion chromatography
X-ray
electron microscopy
PCR
restriction digest
two-hybrid
nucleotide exchange
gel filtration

Software Mentioned

ImageJ
Imaris Bitplane
ASTRA
Imaris
GraphPad Prism
Excel

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