Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss.

TitleRapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss.
Publication TypeJournal Article
Year of Publication2009
AuthorsTain, LS, Mortiboys, H, Tao, RN, Ziviani, E, Bandmann, O, Whitworth, AJ
JournalNat Neurosci
Volume12
Issue9
Pagination1129-35
Date Published2009 Sep
ISSN1546-1726
KeywordsAnimals, Animals, Genetically Modified, Cell Survival, Dopamine, Drosophila, Drosophila Proteins, Fibroblasts, Glutathione Transferase, Humans, Intracellular Signaling Peptides and Proteins, Locomotion, Mitochondria, Muscles, Nerve Degeneration, Neurons, Neuroprotective Agents, Peptide Initiation Factors, Protein-Serine-Threonine Kinases, Sirolimus, Ubiquitin-Protein Ligases
Abstract

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.

DOI10.1038/nn.2372
Alternate JournalNat. Neurosci.
Citation Key10.1038/nn.2372
PubMed ID19684592
PubMed Central IDPMC2745154
Grant List081987 / / Wellcome Trust / United Kingdom
G-0713 / / Parkinson's UK / United Kingdom
G-0715 / / Parkinson's UK / United Kingdom
G-0901 / / Parkinson's UK / United Kingdom
G-1007 / / Parkinson's UK / United Kingdom
G-1202 / / Parkinson's UK / United Kingdom
G-4063 / / Parkinson's UK / United Kingdom
G070091 / / Medical Research Council / United Kingdom
GR077544AIA / / Wellcome Trust / United Kingdom