title: Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure.
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.
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, 07747 Jena, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Beetz
authors.forename: Adam
authors.initials: A
authors.lastname: Johnson
authors.forename: Amber L
authors.initials: AL
authors.lastname: Schuh
authors.forename: Seema
authors.initials: S
authors.lastname: Thakur
authors.forename: Rita-Eva
authors.initials: RE
authors.lastname: Varga
authors.forename: Thomas
authors.initials: T
authors.lastname: Fothergill
authors.forename: Nicole
authors.initials: N
authors.lastname: Hertel
authors.forename: Ewa
authors.initials: E
authors.lastname: Bomba-Warczak
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.forename: Renu
authors.initials: R
authors.lastname: Saxena
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chapman
authors.forename: Erik W
authors.initials: EW
authors.lastname: Dent
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Anjon
authors.initials: A
authors.lastname: Audhya
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005091:Exons / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D008870:Microtubules / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014981:Xenopus; D015027:Zebrafish; D033921:Vesicular Transport Proteins
chemical_list: D009419:Nerve Tissue Proteins; D011506:Proteins; C096163:TFG protein, human; D033921:Vesicular Transport Proteins; C484335:Tfg protein, mouse