Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss.
Mutations in PINK1 and PARK2 cause autosomal recessive parkinsonism, a neurodegenerative disorder that is characterized by the loss of dopaminergic neurons. To discover potential therapeutic pathways, we identified factors that genetically interact with Drosophila park and Pink1. We found that overexpression of the translation inhibitor Thor (4E-BP) can suppress all of the pathologic phenotypes, including degeneration of dopaminergic neurons in Drosophila. 4E-BP is activated in vivo by the TOR inhibitor rapamycin, which could potently suppress pathology in Pink1 and park mutants. Rapamycin also ameliorated mitochondrial defects in cells from individuals with PARK2 mutations. Recently, 4E-BP was shown to be inhibited by the most common cause of parkinsonism, dominant mutations in LRRK2. We also found that loss of the Drosophila LRRK2 homolog activated 4E-BP and was also able to suppress Pink1 and park pathology. Thus, in conjunction with recent findings, our results suggest that pharmacologic stimulation of 4E-BP activity may represent a viable therapeutic approach for multiple forms of parkinsonism.
Tain
Luke S
LS
Medical Research Council Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, UK.
Mortiboys
Heather
H
Tao
Ran N
RN
Ziviani
Elena
E
Bandmann
Oliver
O
Whitworth
Alexander J
AJ
D000818:Animals; D030801:Animals, Genetically Modified; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009132:Muscles / Q000187:drug effects / Q000648:ultrastructure; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010448:Peptide Initiation Factors / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
D004298:Dopamine; D029721:Drosophila Proteins; D005982:Glutathione Transferase; D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D010448:Peptide Initiation Factors; D017346:Protein Serine-Threonine Kinases; D020123:Sirolimus; D044767:Ubiquitin-Protein Ligases; C410006:Thor protein, Drosophila; C111567:parkin protein; C543697:LRRK protein, Drosophila; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase; C487430:park protein, Drosophila
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