Can pharmacological activation of 4E-BP suppress PD?

Tain, L. S. et al. Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nat. Neurosci. 12, 1129–1135 (2009)

Administration of rapamycin suppresses PD-like phenotypes in Drosophila mutants, Tain and colleagues have shown. The drug upregulates the activity of 4E-BP, a protein that is crucial to cellular survival responses and which genetically interacts with PD-related genes.

...4E-BP acts to mediate or promote a survival response implemented on the loss of Parkin or PINK1...

PD is characterized by neurodegeneration in the striatum, leading to progressive loss of motor functions. Mutations in two genes—PARK2 and PINK1—acting via a common pathway can cause the disorder, and Drosophila mutants display PD-like symptoms when these genes are disrupted. Using these flies as a simple animal model, Tain et al. used genetic manipulations to explore PD-related gene function and identify potential therapeutic targets.

A previous genetic screen identified Thor, which encodes the translation inhibitor 4E-BP, as a potential park (the Drosophila equivalent of PARK2) modifier. First, the investigators inhibited Thor in park and Pink1 mutants, which substantially reduced their viability. Second, they induced overexpression of 4E-BP (Figure 1), which suppressed motor and neuronal symptoms of PD. These findings suggest “4E-BP acts to mediate or promote a survival response implemented on the loss of Parkin or PINK1,” according to the researchers. Under normal conditions the Akt1–TOR signalling pathway represses 4E-BP activity. In the mutants, however, this pathway was downregulated, suggesting a mechanism by which the mutant genes might influence PD progression.

Figure 1: Overexpression of 4E-BP in the Drosophila brain.

Confocal micrograph of a wild-type adult Drosophila brain stained with antibodies against tyrosine hydroxylase (green) to highlight dopaminergic neurons, and a marker (red) for targeted expression of transgenes such as 4E-BP to these neuronal populations. Bar 0.1 mm. Image provided by Dr. Alexander Whitworth.

From their genetic manipulations, the investigators identified the Akt1–TOR signaling pathway as a target for pharmacological intervention. Rapamycin is a known chemical modulator of this pathway, and the researchers postulated that this agent would upregulate 4E-BP activity. The researchers supplemented the food of park and Pink1 mutants with rapamycin and found that this suppressed all pathological phenotypes and dopaminergic neurodegeneration in the flies.

Pharmacological stimulation of 4E-BP might warrant further investigation as a potential therapeutic approach in PD according to the authors. Interestingly, previous work has also linked 4E-BP to the most common cause of PD in humans, LRRK2 mutations. Further research into PD-related gene function from Drosophila models should identify additional targets for pharmacological manipulation in this disorder.