LAUSR

Significance Pathological mutations in TFG have been implicated in a variety of neurodegenerative diseases, including early-onset forms of hereditary spastic paraplegia (HSP). In this work, we demonstrate that the TFG p.R106C mutation, which has been identified in several children suffering from HSP, is directly responsible for progressive gait abnormalities, central nervous system pathology, altered muscle electrophysiology, and axonal degeneration within one of the major neuronal pathways involved in coordinated movement. At the cellular level, we additionally demonstrate that the TFG p.R106C mutation impairs two distinct membrane trafficking pathways required for cargo movement within neurons, leading to defects in neuronal function. Our studies strongly suggest that TFG regulates both secretory and endosomal cargo sorting to enable neuronal maintenance.