Rhes Suppression Enhances Disease Phenotypes in Huntington's Disease Mice

Lee, John H.; Sowada, Matthew J.; Boudreau, Ryan L.; Aerts, Andrea M.; Thedens, Daniel R.; Nopoulos, Peg; Davidson, Beverly L.

doi:10.3233/jhd-140094

Cited by 18 publications

(19 citation statements)

References 27 publications

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“…Rhes deletion is neuroprotective in a 3-NP model, ameliorating motor dysfunction and preventing striatal degeneration [78]. Silencing of Rhes in HD genetic mouse models, however, exacerbated both striatal pathology and the "psychiatric" phenotype [79] and, in agreement with these data, its overexpression improved motor function and brain pathology [80].…”

Section: Intrinsic Vulnerability Of Msnsmentioning

confidence: 56%

Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models

Creus-Muncunill

Ehrlich

2019

Neurotherapeutics

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Huntington's disease (HD) is an autosomal dominant disorder caused by an expansion in the trinucleotide CAG repeat in exon-1 in the huntingtin gene, located on chromosome 4. When the number of trinucleotide CAG exceeds 40 repeats, disease invariably is manifested, characterized by motor, cognitive, and psychiatric symptoms. The huntingtin (Htt) protein and its mutant form (mutant huntingtin, mHtt) are ubiquitously expressed but although multiple brain regions are affected, the most vulnerable brain region is the striatum. Striatal medium-sized spiny neurons (MSNs) preferentially degenerate, followed by the cortical pyramidal neurons located in layers V and VI. Proposed HD pathogenic mechanisms include, but are not restricted to, excitotoxicity, neurotrophic support deficits, collapse of the protein degradation mechanisms, mitochondrial dysfunction, transcriptional alterations, and disorders of myelin. Studies performed in cell type-specific and regionally selective HD mouse models implicate both MSN cell-autonomous properties and cell-cell interactions, particularly corticostriatal but also with non-neuronal cell types. Here, we review the intrinsic properties of MSNs that contribute to their selective vulnerability and in addition, we discuss how astrocytes, microglia, and oligodendrocytes, together with aberrant corticostriatal connectivity, contribute to HD pathophysiology. In addition, mHtt causes cell-autonomous dysfunction in cell types other than MSNs. These findings have implications in terms of therapeutic strategies aimed at preventing neuronal dysfunction and degeneration.

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Section: Intrinsic Vulnerability Of Msnsmentioning

confidence: 56%

Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models

Creus-Muncunill

Ehrlich

2019

Neurotherapeutics

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“…Rhes levels are reduced in HD patient caudate nucleus and HD mouse model striatum [ 167 , 168 ]. siRNA knockdown of Rhes exacerbates striatal atrophy and behavioral phenotypes in transgenic HD mice [ 169 ]. In addition, restoring Rhes alleviates motor deficits and brain pathology in HD mice by activating autophagy of mHtt via increasing Beclin-1, and by altering mTORC1-induced gene expressions implicated in promoting mHtt degradation [ 168 ].…”

Section: Striatal Pathologymentioning

confidence: 99%

Striatal Vulnerability in Huntington’s Disease: Neuroprotection Versus Neurotoxicity

Morigaki

Goto

2017

Brain Sciences

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Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat encoding an abnormally long polyglutamine tract (PolyQ) in the huntingtin (Htt) protein. In HD, striking neuropathological changes occur in the striatum, including loss of medium spiny neurons and parvalbumin-expressing interneurons accompanied by neurodegeneration of the striosome and matrix compartments, leading to progressive impairment of reasoning, walking and speaking abilities. The precise cause of striatal pathology in HD is still unknown; however, accumulating clinical and experimental evidence suggests multiple plausible pathophysiological mechanisms underlying striatal neurodegeneration in HD. Here, we review and discuss the characteristic neurodegenerative patterns observed in the striatum of HD patients and consider the role of various huntingtin-related and striatum-enriched proteins in neurotoxicity and neuroprotection.

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“…Accordingly, several studies have demonstrated a protective role of RHES deletion towards HD symptoms in both cellular and animal models (5,14-16), supporting the notion that RHES is a very attractive therapeutic target against HD. In only one report knocking out RHES did not improve HD symptoms (17), likely because of the ability of the C-terminal tail of RHES to activate autophagy, which is protective towards HD (20).…”

Section: Discussionmentioning

confidence: 99%

“…As expected on the basis of these RHES activities, RHES deletion by RNA interference was neuro-protective in HD cellular models (5,14); additionally, motor symptoms were either delayed or reduced in two different RHES knock-out HD mouse models (15,16). Intriguingly, a conflicting result was also reported according to which RHES silencing by inhibitory RNA did not improve motor function in HD mouse models and even increased anxiety and striatal atrophy (17). A possible explanation for this result lies in the fact that RHES has other activities, in addition to SUMO-E3 ligase, which are protective towards HD symptoms.…”

Section: Introductionmentioning

confidence: 99%

“…Autophagy is a lysosomal degradation process implicated in both aging and neurodegeneration, which has been demonstrated to have a protective role in both cellular and animal HD models. The result of RHES dual activity is autophagy activation (20), which explains both the delayed onset of symptoms in HD and the reported worsening of HD symptoms upon RHES knocking-out in mouse models (17).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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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Rhes Suppression Enhances Disease Phenotypes in Huntington's Disease Mice

Cited by 18 publications

References 27 publications

Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models

Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models

Striatal Vulnerability in Huntington’s Disease: Neuroprotection Versus Neurotoxicity

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

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