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.
Background:The striatal-specific protein Rhes is implicated in the selective pathology of HD. Results: Rhes binds Beclin-1 and activates autophagy, a lysosomal degradation pathway critical in aging and neurodegeneration. Conclusion: Rhes-induced autophagy occurs independent of mTOR and JNK-1 signaling and is inhibited by huntingtin. Significance: The restricted expression of Rhes and its effect on autophagy may explain the selective striatal pathology and delayed onset of HD.
Glycosylation is essential to brain development and function, but prior studies have often been limited to a single analytical technique and excluded region- and sex-specific analyses. Here, using several methodologies, we analyze Asn-linked and Ser/Thr/Tyr-linked protein glycosylation between brain regions and sexes in mice. Brain N-glycans are less complex in sequence and variety compared to other tissues, consisting predominantly of high-mannose and fucosylated/bisected structures. Most brain O-glycans are unbranched, sialylated O-GalNAc and O-mannose structures. A consistent pattern is observed between regions, and sex differences are minimal compared to those in plasma. Brain glycans correlate with RNA expression of their synthetic enzymes, and analysis of glycosylation genes in humans show a global downregulation in the brain compared to other tissues. We hypothesize that this restricted repertoire of protein glycans arises from their tight regulation in the brain. These results provide a roadmap for future studies of glycosylation in neurodevelopment and disease.
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