Defining the Mechanism of Meiotic Initiation Through Autophagy Pathway

University Of Kansas Medical Center, Kansas City KS

Investigators

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Abstract

PROJECT SUMMARY Autophagy is the process by which cells degrade and recycle proteins and organelles. Autophagy is defective in AD, and promoting autophagy mitigates AD-associated histopathology in AD models. In AD, the causes and consequences of perturbed autophagy are not entirely understood and the work we now propose will ideally address this knowledge gap. Specifically, stimulated by retinoic acid gene 8 (STRA8) was initially described as a germ cell-specific protein required for meiotic initiation. We are the first to report STRA8 functions as a suppressor of autophagy. As such, Stra8 knockout activates autophagy. Based on this, our R01-HD103888 studies STRA8-mediated suppression of autophagy in germ cell development and meiosis. During our studies, we found STRA8 is unexpectedly expressed in mouse brain cells. Functionally, our data show Stra8-KO mice exhibit increased autophagy in their brains, indicating that the role of STRA8 as a suppressor of autophagy is conserved in both germline and brain cells. Importantly, in aged mouse brains, we found that STRA8 exhibits spindle-shaped accumulation. Moreover, our data show that STRA8 mRNA expression is elevated in autopsied samples from age-matched human AD versus non-AD brains and that STRA8 protein accumulation is detected in human AD brains. These observations link STRA8 to AD, either as a protein whose biology changes as part of a compensatory response in AD or as a protein that contributes to the deterioration of protein homeostasis in AD. As STRA8 acts to suppress autophagy, STRA8 levels increase during aging and in AD brains, and AD brains exhibit defective autophagy and protein stress, either scenario likely perturbs neuronal integrity. This Administrative Supplement to the parent R01-HD103888 grant will extend our studies of STRA8-mediated autophagy suppression from germ cell development and develop a new focus in AD pathogenesis. Our hypothesis is that upregulated STRA8 expression, through its repression of autophagy, can modify AD histology changes, neurodysfunction, neurodegeneration, and behavior in a transgenic AD mouse model. In Aim 1, we will investigate whether Stra8 deletion improves the biochemical and behavioral hallmarks of AD in 5XFAD mice. In Aim 2, we will determine whether ectopic STRA8 overexpression induces protein dyshomeostasis and neuron loss in normal mice and exacerbates AD pathogenesis in 5XFAD mice. Knowledge obtained will inform a potential novel role for STRA8 in AD pathogenesis and address whether STRA8 could serve as a novel AD therapeutic target. Moreover, the literature claims AD neurons re-enter the cell cycle. STRA8’s role in development may inform this aspect of AD and serve as a molecular bridge between aberrant cell cycling and perturbed autophagy.