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

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

Publication date: Dec 01, 2019

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.

Carbo, M., , Brandi, Pascarella, G., Staid, D.S., Colotti, G., Polticelli, F., Ilari, A., and , Morea. Bioinformatics analysis of Ras homologue enriched in the striatum, a potential target for Huntington’s disease therapy. 06749. 2019 Int J Mol Med (44):6.

Concepts Keywords
Aetiological Neurodegeneration
Bioinformatic Ubiquitin
Brain SUMO protein
Corpus Striatum Huntingtin
Cytotoxicity UBE2I
E3 Ligase RASD2
GTP Posttranslational modification
Homologous Proteins
Homologue Branches of biology
Huntingtin
Huntington
Ligase
Molecular Modelling
MRNAs
Neurodegenerative Disorder
Neuroprotective
Neurotoxicity
Peptides
Ras
Rodent
Small Molecule
Striatum
SUMO
Sumoylation
Triplet
Ubiquitin
Wild Type

Semantics

Type Source Name
disease DOID neurotoxicity
gene UNIPROT HTT
disease MESH neurodegenerative disorder
drug DRUGBANK Rasagiline
gene UNIPROT RASD2
gene UNIPROT SLC6A4
gene UNIPROT CD69
gene UNIPROT DNMT1
gene UNIPROT UBE2I
pathway BSID SUMOylation
gene UNIPROT LARGE1
disease MESH development

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