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

53 Pages Posted: 5 Apr 2018 Publication Status: Published

See all articles by Erin L. Slosarek

Erin L. Slosarek

University of Wisconsin - Madison - Department of Biomolecular Chemistry

Amber L. Schuh

University of Wisconsin - Madison - Department of Biomolecular Chemistry

Adam Johnson

University of Wisconsin - Madison - Department of Biomolecular Chemistry

Jennifer Bird

University of Wisconsin - Madison - Department of Biomolecular Chemistry

Matthew Johnson

Florida State University - Department of Chemistry and Biochemistry

E. B. Franke

University of Wisconsin - Madison - Department of Biomolecular Chemistry

Nilakshee Bhattacharya

Florida State University - Department of Chemistry and Biochemistry

Michael G. Hanna

University of Wisconsin - Madison - Department of Biomolecular Chemistry

Jordan E. Burke

University of Wisconsin - Madison - Department of Biochemistry

David A. Ruhl

University of Wisconsin - Madison - Department of Neuroscience

Kyle Quinney

University of Wisconsin - Madison - Department of Biomolecular Chemistry

Edwin R. Chapman

University of Wisconsin - Madison - Department of Neuroscience

Michael D. Sheets

University of Wisconsin - Madison - Department of Biomolecular Chemistry

Samuel E. Butcher

University of Wisconsin - Madison - Department of Biochemistry

Scott M. Stagg

Florida State University - Department of Chemistry and Biochemistry

Anjon Audhya

University of Wisconsin - Madison - Department of Biomolecular Chemistry

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Abstract

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.

Suggested Citation

Slosarek, Erin L. and Schuh, Amber L. and Johnson, Adam and Bird, Jennifer and Johnson, Matthew and Franke, E. B. and Bhattacharya, Nilakshee and Hanna, Michael G. and Burke, Jordan E. and Ruhl, David A. and Quinney, Kyle and Chapman, Edwin R. and Sheets, Michael D. and Butcher, Samuel E. and Stagg, Scott M. and Audhya, Anjon, Pathogenic TFG Mutations Underlying Hereditary Spastic Paraplegia Impair Secretory Protein Trafficking and Axon Fasciculation (2018). Available at SSRN: https://ssrn.com/abstract=3155929 or http://dx.doi.org/10.2139/ssrn.3155929
This version of the paper has not been formally peer reviewed.

Erin L. Slosarek

University of Wisconsin - Madison - Department of Biomolecular Chemistry

United States

Amber L. Schuh

University of Wisconsin - Madison - Department of Biomolecular Chemistry

United States

Adam Johnson

University of Wisconsin - Madison - Department of Biomolecular Chemistry

United States

Jennifer Bird

University of Wisconsin - Madison - Department of Biomolecular Chemistry

United States

Matthew Johnson

Florida State University - Department of Chemistry and Biochemistry

95 Chieftan Way
Tallahassee, FL 32306-4390
United States

E. B. Franke

University of Wisconsin - Madison - Department of Biomolecular Chemistry

United States

Nilakshee Bhattacharya

Florida State University - Department of Chemistry and Biochemistry

95 Chieftan Way
Tallahassee, FL 32306-4390
United States

Michael G. Hanna

University of Wisconsin - Madison - Department of Biomolecular Chemistry

United States

Jordan E. Burke

University of Wisconsin - Madison - Department of Biochemistry

716 Langdon Street
Madison, WI 53706-1481
United States

David A. Ruhl

University of Wisconsin - Madison - Department of Neuroscience

1111 Highland Avenue
Room 5505 WIMR-II
Madison, WI 53705
United States

Kyle Quinney

University of Wisconsin - Madison - Department of Biomolecular Chemistry

United States

Edwin R. Chapman

University of Wisconsin - Madison - Department of Neuroscience

1111 Highland Avenue
Room 5505 WIMR-II
Madison, WI 53705
United States

Michael D. Sheets

University of Wisconsin - Madison - Department of Biomolecular Chemistry

United States

Samuel E. Butcher

University of Wisconsin - Madison - Department of Biochemistry

716 Langdon Street
Madison, WI 53706-1481
United States

Scott M. Stagg

Florida State University - Department of Chemistry and Biochemistry

95 Chieftan Way
Tallahassee, FL 32306-4390
United States

Anjon Audhya (Contact Author)

University of Wisconsin - Madison - Department of Biomolecular Chemistry ( email )

United States