Proteostasis maintenance of neuroreceptors by an ER-phagy receptor

Case Western Reserve University, Cleveland OH

Investigators

Abstract

Project Description Selective autophagy plays an important role in maintaining cellular homeostasis in various organelles. Since proteins in the secretory pathway and membrane proteins must fold into their native structures in the endoplasmic reticulum (ER) before their anterograde trafficking, selective autophagy of the ER, or ER-phagy (reticulophagy), has been recently recognized as an important protein quality control pathway of aggregation-prone proteins in the ER. A key development of ER-phagy is the identification of six specific transmembrane ER-phagy receptors, including CCPG1, the focus of this research. However, there is a significant gap about the role of many of these ER-phagy receptors in physiological and pathophysiological conditions, especially in the central nervous system (CNS). The CNS must maintain a delicate balance between inhibition and excitation. The inhibitory signal is mainly dictated by gamma-aminobutyric acid type A (GABAA) receptors. Proteostasis maintenance of GABAA receptors is critical since their proteostasis defects lead to neurological diseases, such as epilepsy and developmental delay, resulting from variations in genes encoding these neuroreceptors. We and other groups have demonstrated that one major disease-causing mechanism is due to the protein misfolding of these variants in the ER and thus their reduced trafficking to the cell surface for function. Preliminary data demonstrated that GABAA receptor variants that aggregate in the ER are targeted to the lysosome for degradation; furthermore, among the known six membrane ER-phagy receptors, only CCPG1 interacts with the variants to promote clearance. However, the role of CCPG1 in the CNS is unknown yet. Therefore, based on preliminary data, we hypothesized that CCPG1 directs aggregation-prone GABAA receptor variants in the ER to the ER-phagy pathway, and loss of function of CCPG1 leads to protein aggregation and proteostasis deficiency in neurons. We proposed to test the hypothesis with the following specific aims by combining approaches in cell biology and electrophysiology. Here, in Specific Aim 1, we will elucidate CCPG1-mediated ER-phagy pathway for pathogenic neuroreceptor variants. In Specific Aim 2, we will determine the effect of CCPG1 on proteostasis maintenance of neurons.