TRAPPing a neurological disorder: from yeast to humans

The modular complex TRAPP acts as an activator of a subgroup of Ypt/RAB GTPases. The substrate GTPases and TRAPP are conserved from yeast to human cells, required for secretion and macroautophagy/autophagy and implicated in human disease. All TRAPP complexes contain four core subunits essential for cell viability, and until recently there were no human diseases associated with any core TRAPP subunit. Recently, we reported a neurological disorder associated with a pathogenic variant of the core TRAPP subunit TRAPPC4. This variant results in lower levels of full-length TRAPPC4 protein and the TRAPP complex. A conditional mutation of the yeast homolog of TRAPPC4, Trs23, also results in a lower level of the protein and the TRAPP complex. Phenotypic analysis of the yeast mutant cells reveals a minor defect in secretion and a major defect in autophagy. Similarly, primary fibroblasts derived from human patients also exhibit minor and severe defects in secretion and autophagy, respectively. We propose that the autophagy defect caused by the pathogenic-TRAPPC4 variant results in the severe neurological disorder. Moreover, we hypothesize that low levels of the core TRAPP complex are more detrimental to autophagy than to secretion, and that the long-term autophagy defect is especially harmful to neuronal cells.