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

Abstract

Mutations in PINK1 and parkin cause autosomal recessive parkinsonism, a neurodegenerative disorder characterized by the loss of dopaminergic neurons. To highlight potential therapeutic pathways we have identified factors that genetically interact with parkin/PINK1. Here we report that overexpression of the translation inhibitor 4E-BP can suppress all pathologic phenotypes including degeneration of dopaminergic neurons in Drosophila. 4E-BP is activated in vivo by the TOR inhibitor rapamycin, which we find can potently suppress pathology in PINK1/parkin mutants. Rapamycin also ameliorates mitochondrial defects in cells from parkin-mutant patients. Recently, 4E-BP was shown to be inhibited by the most common cause of parkinsonism, dominant mutations in LRRK2. Here we further show that loss of the Drosophila LRRK2 homolog activates 4E-BP and is also able to suppress PINK1/parkin 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.

Biosynthesis of the immunosuppressants FK506, FK520, and rapamycin involves a previously undescribed family of enzymes acting on chorismate

“…The selective inhibition of mTOR by the rapamycin-FKBP12 complex in cancer cells underlies the current clinical use of semisynthetic analogs of rapamycin against several malignancies including advanced renal cancer (5, 7). FK506 and rapamycin analogs also show potential therapeutic value against stroke (8), nerve degeneration (9), Parkinson disease (10), and Alzheimer's disease (11,12). Rapamycin has recently been shown to extend the average life span of genetically heterogeneous mice, even when fed late in life (13,14).…”

Optimal dietary protein level improved growth, disease resistance, intestinal immune and physical barrier function of young grass carp (Ctenopharyngodon idella)

“…Additionally, TOR could activate S6K1 [75] and inhibit 4E-BP [76] expression in Drosophila. In the present study, optimal dietary protein levels up-regulated TOR and S6K1 mRNA levels and downregulated 4E-BP2 mRNA levels, which had no significant influence on the 4E-BP1 mRNA levels in three intestinal segments of young grass carp.…”

PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

“…In contrast, Sir2 overexpression does not rescue parkin mutant phenotypes, and Sir2 deletion only inhibits the development of parkin mutants but not PINK1 mutants. Moreover, the mRNA expression of super oxide dismutase 2 (SOD2) and 4E-binding protein (4EBP), the FOXO target genes with mitochondrial protective roles (Kops et al, 2002;Puig et al, 2003;Tain et al, 2009;Zid et al, 2009), are substantially reduced in PINK1 mutants but are normal in parkin mutants (Koh et al, 2012), suggesting that Sir2 and FOXO act in mitochondrial protection in parallel with Parkin. Consistently, Sir2 and FOXO mutants exhibit DA neuron degeneration very similar to that of PINK1 mutants.…”