Bioinformatics analysis of Ras homologue enriched in the striatum, a potential target for Huntington's disease therapy

Carbo,Miriam; Brandi,Valentina; Pascarella,Gianmarco; Staid,David  Sasah; Colotti,Gianni; Polticelli,Fabio; Ilari,Andrea; Morea,Veronica

doi:10.3892/ijmm.2019.4373

Bioinformatics analysis of Ras homologue enriched in the striatum, a potential target for Huntington's disease therapy

Authors:
- Miriam Carbo
- Valentina Brandi
- Gianmarco Pascarella
- David Sasah Staid
- Gianni Colotti
- Fabio Polticelli
- Andrea Ilari
- Veronica Morea
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Affiliations: Department of Biochemical Sciences ‘A. Rossi Fanelli’, Sapienza University, I‑00185 Rome, Italy, Department of Sciences, Roma Tre University, I‑00159 Rome, Italy, Institute of Molecular Biology and Pathology of The National Research Council of Italy, I‑00185 Rome, Italy
Published online on: October 15, 2019 https://doi.org/10.3892/ijmm.2019.4373
Pages: 2223-2233
Copyright: © Carbo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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