Ras homolog enriched in striatum (RASD2) (RASD2)

Ras homolog enriched in striatum (Rhes), encoded by the RASD2 gene, is a small GTPase predominantly expressed in the striatal region of the brain (UniProt Q96D21). It functions as a unique SUMO E3 ligase that attaches Small Ubiquitin-like Modifier (SUMO) to mutant Huntingtin (mHTT) protein, which significantly increases the protein's solubility and cytotoxicity, leading to the selective neurodegeneration seen in Huntington's disease (Subramaniam et al., 2009, Science). Beyond sumoylation, Rhes interacts with and activates the mechanistic target of rapamycin (mTOR), thereby inhibiting autophagy and promoting the accumulation of toxic protein aggregates (Mealer et al., 2014, Journal of Neuroscience). Rhes also plays a critical role in modulating dopamine D2 receptor signaling, making it a key factor in the development of levodopa-induced dyskinesia in Parkinson's disease models (Ghiglieri et al., 2015, Frontiers in Cellular Neuroscience). Due to its highly localized expression and multi-faceted role in neurodegenerative pathology, Rhes is considered a high-priority therapeutic target for Huntington's disease and other movement disorders (Napolitano et al., 2019, Cells). Current therapeutic strategies under investigation include the use of antisense oligonucleotides and RNA interference to silence Rhes expression and provide neuroprotection (Swarnkar et al., 2015, Neurobiology of Disease).

Other names

RhesRas-related dexamethasone-induced protein 2TEMPIGTP-binding protein Rhes

Reduction of Rhes protein expression to decrease sumoylation of mutant Huntingtin protein and restore autophagy via mTOR modulation.