Rhes, a striatal-enriched small G protein, mediates mTOR signaling and L-DOPA–induced dyskinesia

Abstract

L–DOPA–induced dyskinesia, the rate–limiting side–effect in the therapy of Parkinson’s Disease, is mediated by activation of mTOR signaling in the striatum. We show that Rhes, a striatal–specific protein, binds to and activates mTOR. Moreover, Rhes deleted mice manifest reduced striatal mTOR signaling and diminished dyskinesia but maintain motor improvement upon L–DOPA treatment, implying therapeutic benefit for Rhes–binding drugs.

Rhes, a Striatal-selective Protein Implicated in Huntington Disease, Binds Beclin-1 and Activates Autophagy

“…Competitive inhibition of Beclin-1/Bcl-2 binding occurs with many other important regulators of autophagy, including HMGB1, UVRAG, and Atg14L/Barkor (31). Rhes-induced autophagy is independent of mTOR, as the effect is not inhibited by rapamycin and occurs in the opposite direction as what would be predicted based our previous finding that Rhes activates mTOR (24,34). Thus, Rhes can affect autophagy through two independent pathways (Fig.…”

“…One important regulator of autophagy is mTOR, whose activation classically inhibits autophagy (23). We recently discovered that Rhes shares with Rheb the ability to bind and activate mTOR (24). Additionally, Rhes-deleted mice have markedly reduced L-DOPA-induced dyskinesia, a side effect of chronic L-DOPA (L-3,4-dihydroxyphenylalanine) treatment caused by aberrant mTOR signaling in the striatum (24,25).…”

“…We recently discovered that Rhes shares with Rheb the ability to bind and activate mTOR (24). Additionally, Rhes-deleted mice have markedly reduced L-DOPA-induced dyskinesia, a side effect of chronic L-DOPA (L-3,4-dihydroxyphenylalanine) treatment caused by aberrant mTOR signaling in the striatum (24,25). Thus, Rhes plays a physiologic role in striatal mTOR activation and would be predicted to inhibit autophagy secondary to mTOR activation.…”

p11 modulates L-DOPA therapeutic effects and dyskinesia via distinct cell types in experimental Parkinsonism

“…To further examine the role of D1R-containing cells in the development of AIMs and to obtain some mechanistic insight, we coadministered L-DOPA with vehicle or rapamycin, an mTOR inhibitor. Rapamycin blocks L-DOPA-induced mTOR/ Akt/Rhes signaling in D1R-containing cells and thereby counteracts AIMs (15,19). The fact that rapamycin was inefficient in counteracting AIMs in D1R-p11cKO mice indicates that interference with mTOR/Akt/Rhes signaling may underlie p11-dependent modulation of AIMs.…”

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…Whether blockade of mTOR would also alleviate established LID remains unknown. Attenuating mTOR activation by switching off the protein Ras homolog enriched in striatum (Rhes) alleviated, but did not abolish, development of LI-AIMs in the 6-OHDA-lesioned mouse (Subramaniam et al, 2011).…”