Autophagy and Receptor-Induced Neurodegeneration

Abstract

Much attention has focused on the role of apoptosis in neurodegenerative diseases. Yue et al. present evidence that an alternative form of death--characterized by excessive autophagy--may also be a critical factor. In autophagic death, the cytoplasmic matrix and organelles are engulfed in autophagosomes and autophagic vacuoles and degraded in lysosomes. Mice that have a mutation in the glutamate receptor subunit GluRδ2 have constitutively active cation-permeable glutamate receptor channels and are called lurcher mice--so-named for their ataxic behavior, which results from degeneration of the cerebellar cortex. Yue et al. used a yeast two-hybrid screen to find proteins that interacted with the cytoplasmic tail of the GluRδ2 subunit and identified a protein called nPIST. The nPIST protein has properties that suggest it functions as an adaptor, possibly mediating protein-protein interactions at the receptor. A second two-hybrid screen, this time with coiled-coil domains of PIST, identified Beclin1, a protein previously implicated in control of membrane dynamics during autophagy. When transfected into cultured 293 cells, nPIST that lacked its PDZ domain (a likely site for interaction with other proteins) synergized with Beclin 1 to cause autophagy. Autophagy was also detected in dying Purkinje cells in the cerebellum of lurcher mice. The results suggest that inappropriate activation of glutamate receptors may lead to autophagic neurodegeneration through signals mediated by proteins clustered at the receptor, including nPIST and Beclin 1. Intriguingly, Beclin1 has also been shown to associate with members of the Bcl2 family of proteins, which regulate apoptosis. The authors note that inclusion of Bcl2 family members in a complex with the GluRδ2 subunit could provide coordinated regulation of both autophagy and apoptosis in the compromised Purkinje cells of lurcher mice. Z. Yue, A. Horton, M. Bravin, P. L. DeJager, F. Selimi, N. Heintz, A novel protein complex linking the δ2 glutamate receptor and autophagy: Implications for neurodegeneration in lurcher mice, Neuron 35 , 921-933 (2002). [Online Journal]