Open Close
Reference
Citation
Tain, L.S., Mortiboys, H., Tao, R.N., Ziviani, E., Bandmann, O., Whitworth, A.J. (2009). Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss.  Nat. Neurosci. 12(9): 1129--1135.
FlyBase ID
FBrf0208620
Publication Type
Research paper
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.

PubMed ID
PubMed Central ID
PMC2745154 (PMC) (EuropePMC)
Associated Information
Comments
Associated Files
Other Information
Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Nat. Neurosci.
    Title
    Nature Neuroscience
    Publication Year
    1998-
    ISBN/ISSN
    1097-6256
    Data From Reference
    Alleles (10)
    Genes (9)
    Human Disease Models (3)
    Cell Lines (1)
    Insertions (1)
    Transgenic Constructs (5)