012-22 – Trappc9 deficiency in mice recapitulates human disorder of microcephaly and is associated with lipid droplet abnormalities in neurons.

Transport Protein Particle Complex Subunit 9 (Trappc9) is a TRAPPII complex subunit that acts as a tethering factor in intracellular trafficking processes. Trappc9 also functions as a guanine nucleotide exchange factor to activate Rab18, a protein that regulates lipid droplet (LD) metabolism. It is known that Rab18 interacts with Plin2 and ACSL3 around LDs. Lipids are vital for the nervous system, and LD abnormalities have been associated with various neuropathologies. Homozygous TRAPPC9 mutations in humans cause microcephaly, intellectual impairment and obesity. White matter abnormalities, cerebellar atrophy, and a thinned corpus callosum have all been reported in patients with this condition. Currently, the mechanism of Trappc9 involvement in these phenotypes has not been fully understood.

This study uses Trappc9 knockout (KO) mice to characterise LDs in primary neuron cultures and the general phenotype in brain development and weight regulation. These mice showed ~10% reduction in brain weight at weaning age and in adulthood, but not at birth. Furthermore, KO mice on chow diet showed a gradual increase in body weight which was more significant in females than males. RNAscope analysis of adult mouse brain sections showed expression of Trappc9 in the cerebral cortex, hippocampus and hypothalamus. Analysis of primary neuronal cultures following oleic acid treatment showed abnormalities of lipid droplets number and size in KO cells. These accumulations were accompanied by mis-localisation of Plin2 around LDs. Neuronal viability in response to LD accumulation was assessed in vitro and showed no difference between genotypes.

Our data showed that Trappc9 loss in mice results in postnatal-onset microcephaly and increased obesity, mimicking human illness symptoms. These findings could be linked to a malfunction of lipid droplet homeostasis. Further investigation is warranted to understand the role of Trappc9 and lipid droplets in neural cell functions.