Autophagy and Receptor-Induced Neurodegeneration

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Science  13 Sep 2002:
Vol. 297, Issue 5588, pp. 1773
DOI: 10.1126/science.297.5588.1773b

Much attention has focused on the role of apoptosis in neurodegenerative diseases. An alternative form of death—autophagic death—may also be a critical factor. In autophagic death, organelles and cytoplasm are engulfed by autophagosomes and degraded. Lurcher mice (named for their ataxic behavior due to degeneration of the cerebellar cortex) have a mutation in the glutamate receptor subunit GluR2.

Yue et al. used a yeast two-hybrid screen to find proteins that interacted with the cytoplasmic tail of the GluR2 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 using the coiled-coil domains of nPIST, 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. Thus, 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 Bcl-2 family of pro-apoptotic proteins and could perhaps provide a mechanism for coordinated regulation of autophagy and apoptosis in the compromised Purkinje cells of lurcher mice. — LBR

Neuron35, 921 (2002).

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