A novel protein complex linking the delta 2 glutamate receptor and autophagy: implications for neurodegeneration in lurcher mice.
Autophagy is a pathway for bulk degradation of subcellular constituents that is hyperactivated in many neurodegenerative conditions. It has been considered a second form of programmed cell death. Death of cerebellar Purkinje cells in lurcher animals is due to a mutation in GluRdelta2 that results in its constitutive activation. Here we have identified protein interactions between GluRdelta2, a novel isoform of a PDZ domain-containing protein (nPIST) that binds to this receptor, and Beclin1. nPIST and Beclin1 can synergize to induce autophagy. GluRdelta2(Lc), but not GluRdelta2(wt), can also induce autophagy. Furthermore, dying lurcher Purkinje cells contain morphological hallmarks of autophagic death in vivo. These results provide strong evidence that a direct link exists between GluRdelta2(Lc) receptor and stimulation of the autophagic pathway in dying lurcher Purkinje cells.
Yue
Zhenyu
Z
Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Horton
Antony
A
Bravin
Monica
M
DeJager
Philip L
PL
Selimi
Fekrije
F
Heintz
Nathaniel
N
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D000077614:Golgi Matrix Proteins; D006801:Humans; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D051379:Mice; D008818:Mice, Neurologic Mutants; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D017470:Receptors, Glutamate / Q000737:chemistry / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D002352:Carrier Proteins; C434484:GOPC protein, human; D000077614:Golgi Matrix Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D020033:Protein Isoforms; D011506:Proteins; D017470:Receptors, Glutamate; C107913:glutamate receptor delta 2