Microcephaly with a disproportionate hippocampal reduction, stem cell loss and neuronal lipid droplet symptoms in
Sultan Aljuraysi1, Mark Platt2, Michela Pulix3
1Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK; Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
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 magnetic resonance imaging (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.
Insights
Mutations in TRAPPC9 cause neurodevelopmental disorders. TRAPPC9 deficiency in mice leads to microcephaly, brain abnormalities, and behavioral deficits, potentially linked to lipid droplet dysfunction.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Mutations in the human gene TRAPPC9 are linked to a neurodevelopmental disorder characterized by microcephaly and intellectual disability.
- TRAPPC9 is a subunit of the TrappII complex, which interacts with Rab proteins involved in intracellular transport and lipid droplet (LD) association.
Purpose of the Study:
- To investigate the neurobiological consequences of TRAPPC9 deficiency using a mouse model.
- To explore the role of TRAPPC9 in brain development, cellular processes, and potential links to lipid metabolism.
Main Methods:
- Utilized TRAPPC9 knock-out (KO) mice for in vivo studies.
- Employed non-invasive imaging techniques including MRI and diffusion tensor imaging.
- Conducted cellular analysis of primary hippocampal neurons and assessed behavioral phenotypes in KO mice.
Main Results:
- TRAPPC9 KO mice exhibited postnatal microcephaly affecting both grey and white matter, with significant hippocampal volume reduction.
- Imaging revealed impaired white matter integrity, and behavioral tests indicated deficits in exploration, learning, and memory.
- TRAPPC9-deficient neurons showed altered lipid droplet accumulation and reduced Perilipin-2 coating; KO mice developed obesity, more pronounced in females.
Conclusions:
- TRAPPC9 deficiency causes significant neurodevelopmental and behavioral abnormalities in mice, mirroring human disorders.
- Dysregulation of lipid droplet homeostasis, in addition to vesicle transport defects, may underlie the neurobiological symptoms of TRAPPC9 deficiency.
