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

Aljuraysi, Sultan, Platt, Mark, Pulix, Michela, Poptani, Harish ORCID: 0000-0002-0593-3235 and Plagge, Antonius ORCID: 0000-0001-6592-1343 (2023) Microcephaly with a disproportionate hippocampal reduction, stem cell loss and neuronal lipid droplet symptoms inTrappc9KO mice [Preprint]

PDF BIORXIV-2023-567859v1-Plagge.pdf - Preprint version Download (3MB) | Preview

Abstract

Mutations of the human TRAFFICKING 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 characterise Trappc9 knock-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 vivo MRI 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. Trappc9 KOs 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, Trappc9 KOs 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.

Item Type:	Preprint
Uncontrolled Keywords:	3101 Biochemistry and Cell Biology, 32 Biomedical and Clinical Sciences, 31 Biological Sciences, Stem Cell Research, Rare Diseases, Neurosciences, Biomedical Imaging, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Pediatric Research Initiative, Congenital Structural Anomalies, Mental Health, 2.1 Biological and endogenous factors, Neurological
Divisions:	Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	21 Nov 2023 11:53
Last Modified:	30 Jan 2026 01:20
DOI:	10.1101/2023.11.20.567859
Related Websites:	Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3176932
Disclaimer:	The University of Liverpool is not responsible for content contained on other websites from links within repository metadata. Please contact us if you notice anything that appears incorrect or inappropriate.