Restriction of trophic factors and nutrients induces PARKIN expression.
Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder and manifests at old age. While many details of its pathogenesis remain to be elucidated, in particular the protein and mitochondrial quality control during stress responses have been implicated in monogenic PD variants. Especially the mitochondrial kinase PINK1 and the ubiquitin ligase PARKIN are known to cooperate in autophagy after mitochondrial damage. As autophagy is also induced by loss of trophic signaling and PINK1 gene expression is modulated after deprivation of cytokines, we analyzed to what extent trophic signals and starvation stress regulate PINK1 and PARKIN expression. Time course experiments with serum deprivation and nutrient starvation of human SH-SY5Y neuroblastoma cells and primary mouse neurons demonstrated phasic induction of PINK1 transcript up to twofold and PARKIN transcript levels up to sixfold. The corresponding threefold starvation induction of PARKIN protein was limited by its translocation to lysosomes. Analysis of primary mouse cells from PINK1-knockout mice indicated that PARKIN induction and lysosomal translocation occurred independent of PINK1. Suppression of the PI3K-Akt-mTOR signaling by pharmacological agents modulated PARKIN expression accordingly. In conclusion, this expression survey demonstrates that PARKIN and PINK1 are coregulated during starvation and suggest a role of both PD genes in response to trophic signals and starvation stress.
Experimental Neurology, Department of Neurology, University Medical School, Goethe University, Heinrich-Hoffmann-Str. 7, 60528, Frankfurt am Main, Germany.
M
M
Klinkenberg
S
S
Gispert
J A
JA
Dominguez-Bautista
I
I
Braun
G
G
Auburger
M
M
Jendrach
D000818:Animals; D002460:Cell Line; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013217:Starvation; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
D036341:Intercellular Signaling Peptides and Proteins; D011494:Protein Kinases; D011993:Recombinant Fusion Proteins; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein