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Updated: Jan 5, 2026
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Bioinformatics analysis of Ras homologue enriched in the striatum, a potential target for Huntington's disease
Miriam Carbo1, Valentina Brandi2, Gianmarco Pascarella1
1Department of Biochemical Sciences 'A. Rossi Fanelli', Sapienza University, I‑00185 Rome, Italy.
Insights
Researchers identified Ras Homolog Enriched in Striatum (RHES) as a potential target for Huntington's disease (HD) therapy. Inhibiting RHES sumoylation may offer a new treatment strategy for this incurable neurodegenerative disorder.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Huntington's disease (HD) is a fatal neurodegenerative disorder caused by CAG triplet expansion in the huntingtin gene, leading to toxic soluble mutant huntingtin (mHtt).
- The corpus striatum is selectively degraded in HD, despite ubiquitous huntingtin protein expression.
- Ras Homolog Enriched in Striatum (RHES) was identified as a striatum-specific protein with a small ubiquitin-like modifier (SUMO)-E3 ligase function.
Purpose of the Study:
- To investigate the 3D structure and function of RHES in the context of Huntington's disease.
- To identify RHES regions involved in interactions with mHtt and the SUMO-E2 ligase Ubc9.
- To design peptides targeting RHES interactions for potential therapeutic development.
Main Methods:
- Bioinformatic analyses and molecular modeling were employed to study RHES structure and function.
- Identification of RHES interaction sites with mHtt and Ubc9.
- Design of inhibitory peptides targeting RHES-mHtt and RHES-Ubc9 interactions.
Main Results:
- RHES efficiently sumoylates mHtt, protecting it from degradation and increasing soluble mHtt levels.
- Specific RHES regions interacting with mHtt and Ubc9 were identified through computational analyses.
- Peptides designed to inhibit these interactions were proposed as a basis for developing small molecule inhibitors.
Conclusions:
- RHES plays a critical role in mHtt metabolism and represents a promising therapeutic target for Huntington's disease.
- Inhibiting RHES sumoylation activity could reduce toxic soluble mHtt, offering a novel treatment strategy.
- Further development of RHES sumoylation inhibitors may lead to effective therapies for Huntington's disease.
Abstract:
Huntington's disease (HD) is a lethal neurodegenerative disorder for which no cure is available yet. It is caused by abnormal expansion of a CAG triplet in the gene encoding the huntingtin protein (Htt), with consequent expansion of a polyglutamine repeat in mutated Htt (mHtt). This makes mHtt highly unstable and aggregation prone. Soluble mHtt is linked to cytotoxicity and neurotoxicity, whereas mHtt aggregates are thought to be neuroprotective. While Htt and mHtt are ubiquitously expressed throughout the brain and peripheral tissues, HD is characterized by selective degradation of the corpus striatum, without notable alterations in peripheral tissues. Screening for mRNAs preferentially expressed in rodent striatum led to the discovery of a GTP binding protein homologous to Ras family members. Due to these features, the newly discovered protein was termed Ras Homolog Enriched in Striatum (RHES). The aetiological role of RHES in HD has been ascribed to its small ubiquitin‑like modifier (SUMO)‑E3 ligase function. RHES sumoylates mHtt with higher efficiency than wild‑type Htt, thereby protecting mHtt from degradation and increasing the amounts of the soluble form. Although RHES is an attractive target for HD treatment, essential information about protein structure and function are still missing. With the aim of investigating RHES 3D structure and function, bioinformatic analyses and molecular modelling have been performed in the present study, based on which, RHES regions predicted to be involved in the interaction with mHtt or the SUMO‑E2 ligase Ubc9 have been identified. These regions have been used to design peptides aimed at inhibiting RHES interactions and, therefore, mHtt sumoylation; in turn, these peptides will be used to develop small molecule inhibitors by both rational design and virtual screening of large compound libraries. Once identified, RHES sumoylation inhibitors may open the road to the development of therapeutic agents against the severe, and currently untreatable, HD.
