Induction of macroautophagy by overexpression of the Parkinson's disease-associated GPR37 receptor.
The orphan G-protein-coupled receptor 37 (GPR37) is a substrate of parkin, and its insoluble aggregates accumulate in brain tissue samples of Parkinson's disease patients, including Lewy bodies and neurites. Parkin activates the clearance of the unfolded receptor, while the overexpression of GPR37, in the absence of parkin, can lead to unfolded protein-induced cell death. We found that overexpression of the human GPR37 receptor in HEK293 cells and consequent activation of an endoplasmic reticulum (ER) stress response had effects comparable to starvation, in inducing the cellular autophagic pathway. Treatment with specific modulators provided further evidence for the autophagic clearance of the overexpressed GPR37 protein, in detergent-soluble and -insoluble fractions, as confirmed by the conversion of the microtubule-associated protein 1, light chain 3 (LC3)-I marker to its LC3-II isoform. Furthermore, Gpr37-null mutant mice displayed consistent alterations of ER stress and autophagic pathway markers in brain tissue samples. These findings show that GPR37 overexpression per se can induce cellular autophagy, which may prevent the selective degeneration of GPR37-expressing neurons, as reported for Parkinson's and related neurodegenerative diseases.
Marazziti
Daniela
D
Istituto di Biologia Cellulare-CNR, Campus A. Buzzati-Traverso, Via E. Ramarini 32, I-00015 Monterotondo Scalo, Rome, Italy.
Di Pietro
Chiara
C
Golini
Elisabetta
E
Mandillo
Silvia
S
Matteoni
Rafaele
R
Tocchini-Valentini
Glauco P
GP
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007790:Lactosylceramides / Q000737:chemistry / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism
D015415:Biomarkers; D000091342:Endoplasmic Reticulum Chaperone BiP; C480827:GPR37 receptor, human; C509804:Gpr37 protein, mouse; D006360:Heat-Shock Proteins; D007790:Lactosylceramides; D018832:Molecular Chaperones; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D043562:Receptors, G-Protein-Coupled; C025575:lactotriaosylceramide; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex; C078846:epoxomicin