| Autor: |
Edwin R. Chapman, Amber L. Schuh, Jennifer Bird, Samuel E. Butcher, Anjon Audhya, E. B. Franke, Erin L. Slosarek, Scott M. Stagg, Michael D. Sheets, David A. Ruhl, Kyle Quinney, Jordan E. Burke, Michael G. Hanna, Adam Johnson, Nilakshee Bhattacharya, Matthew C. Johnson |
| Rok vydání: |
2018 |
| Předmět: |
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| Zdroj: |
SSRN Electronic Journal. |
| ISSN: |
1556-5068 |
| DOI: |
10.2139/ssrn.3155929 |
| Popis: |
Length-dependent axonopathy of the corticospinal tract causes lower limb spasticity and weakness and is characteristic of several neurological disorders, including hereditary spastic paraplegia (HSP) and amyotrophic lateral sclerosis (ALS). Mutations in tropomyosin-receptor kinase fused gene (TFG) have been implicated in both disease states, but the pathomechanisms by which these alterations cause neuropathy remain unclear. Here, we biochemically and genetically define the impact of a mutation within the coiled coil domain of TFG, 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). Moreover, 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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