Microcephaly with a disproportionate hippocampal reduction, stem cell loss and neuronal lipid droplet symptoms inTrappc9KO mice

Abstract

Mutations of the humanTRAFFICKING PROTEIN PARTICLE COMPLEX SUBUNIT 9(TRAPPC9) cause a neurodevelopmental disorder characterised by microcephaly and intellectual disability. Trappc9 constitutes a subunit specific to the intracellular membrane-associated TrappII complex. The TrappII complex interacts with Rab11 and Rab18, the latter being specifically associated with lipid droplets (LDs). Here we used non-invasive imaging to characteriseTrappc9knock-out (KO) mice as a model of the human hereditary disorder. KOs developed postnatal microcephaly with many grey and white matter regions being affected.In vivoMRI identified a disproportionately stronger volume reduction in the hippocampus, which was associated with a significant loss of Sox2-positive neural stem and progenitor cells. Diffusion Tensor imaging indicated a reduced organisation or integrity of white matter areas.Trappc9KOs displayed behavioural abnormalities in several tests related to exploration, learning and memory. Trappc9-deficient primary hippocampal neurons accumulated a larger LD volume per cell following Oleic Acid stimulation, and the coating of LDs by Perilipin-2 was much reduced. Additionally,Trappc9KOs developed obesity, which was significantly more severe in females than in males. Our findings indicate that, beyond previously reported Rab11-related vesicle transport defects, dysfunctions in LD homeostasis might contribute to the neurobiological symptoms of Trappc9 deficiency.

Chronic pharmacologic manipulation of dopamine transmission ameliorates metabolic disturbance in syndrome caused by mutated trappc9

“…While Dlg2 and Gpm6a were also decreased in male trappc9 KO mice, the levels of Unc13c, Synpo1, and Insyn1 were comparable relative to their levels in male WT mice (Figure 6D, 6E). It is not clear whether this divergence is related to the sex difference in time of onset of obesity and severity of phenotypes between female and male trappc9 KO mice ( 24, 27 ). Notably, the trend of change in protein levels was opposite to that in gene transcripts, likely because compensatory effects have been developed in trappc9 KO mice.…”

“…These human studies define trappc9 to be a risk factor for obesity. Consistently, all four trappc9 mutant mouse lines available to date appear overweight postnatally (24)(25)(26)(27). However, how trappc9 mutations cause obesity is an enigma.…”

“…We and others recently generated genetically modified mice with loss-of-function mutations in the mouse trappc9 gene; homozygous mutant or knockout (KO) mice of all these 4 mouse lines show deficits in a wide range of behaviors and abnormal changes in various brain structures ( 24–27 ), replicating what happens in patients. Compared with their wildtype (WT) counterparts, trappc9 KO mice are normal in gaining body weight in early developmental periods but appear overweight shortly after being weaned ( 24–27 ). Adipose-derived stromal or stem cells (ASCs) play an important role in the development of obesity by remodeling adipose tissues through generating new adipocytes and secreting bioactive molecules to maintain the immunological homeostasis in adipose tissues ( 28–31 ).…”

“…Exactly how trappc9 variations trigger the onset of obesity and NAFLD is unknown. We and others recently generated genetically modified mice with loss-of-function mutations in the mouse trappc9 gene; homozygous mutant or knockout (KO) mice of all these 4 mouse lines show deficits in a wide range of behaviors and abnormal changes in various brain structures (24)(25)(26)(27), replicating what happens in patients. Compared with their wildtype (WT) counterparts, trappc9 KO mice are normal in gaining body weight in early developmental periods but appear overweight shortly after being weaned (24)(25)(26)(27).…”

Chronic pharmacologic manipulation of dopamine transmission ameliorates metabolic disturbance in Trappc9-linked brain developmental syndrome

“…However, it is not clear how trappc9 genetic variations trigger the development of obesity and NAFLD. We and others recently generated genetically modified mice with a loss-of-function mutation in the mouse trappc9 gene; homozygous mutant or knockout (KO) mice of all these mouse lines show deficits in a wide range of behaviors and malformation of various brain structures replicating what happens in patients (19)(20)(21)(22). All these trappc9 KO mouse lines develop overweight postnatally; female KO mice become overweight earlier than male KO mice (19)(20)(21)(22).…”