Localization of Frontotemporal Dementia Risk Gene RAB38 to Glutamatergic Neurons: Implications for Selective Neuronal Vulnerability

Overview

Frontotemporal dementia (FTD) is a leading type of early -onset dementia caused by progressive neurodegeneration in the frontal and temporal lobes of the brain, resulting in significant alterations in behavior, personality, and language. Neuronal loss predominantly affects the pyramidal cells in Layer Vof the neocortex, leading to the death of glutamatergic neurons. This study targeted the selective neuronal death observed in FTD, focusing on pyramidal cells in neocortical Layer V. Utilizing the Human Prote in Atlas and online databases, Rab38 emerged as a potential risk gene due to its colocalization with marker genes. To explore Rab38's role in selective neuronal vulnerability, RNAscope in situ hybridization was used to detect the presence of Rab38 and marker genes (Slc17a7 for glutamatergic neurons, Fezf2 for Layer V pyramidal neurons) in mouse tissue. Confocal microscopy and analysis of the slides using Cell Profiler identified Fezf2 and Rab38 in a subset of pyramidal neurons, establishing statistically si gnificant variation in Rab38 and Fezf2 RNA expression between different mice. The relative frequency distribution of Fezf2 and Rab38 pixel densities per cell confirmed the presence of Rab38 in Layer Vpyramidal neurons and revealed a higher proportion of n eurons with Rab38 but without Fezf2, contrary to initial expectations. Afterward, a comprehensive analysis of the expression levels of Rab38 and Fezf2 was conducted, demonstrating colocalization and a positive correlation. Further investigation into Rab38 expression across low, medium, and high Fezf2-expressing populations in Layer Vpyramidal neurons indicated variability in gene expression, highlighting potential influences from technical or biological factors.

Competition history

• JSHS 2024 Category not listed

Resources

• National JSHS abstract book ↗

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