Subramaniam S, Sixt KM, Barrow R, Snyder SH.
Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity.
Science. 2009 Jun 5;324(5932):1327-30.
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Huntington disease (HD) is an ultimately fatal genetic neurodegenerative disease with a triad of cognitive, neuropsychiatric, and motor symptoms caused by the polyglutamine expansion in the coding region of the Huntingtin gene. Despite intense research in the field, there are currently no disease-modifying treatments for HD and treatment remains limited to management of symptoms. Since the discovery of the gene, the search for anatomical or molecular explanations for the preferential loss of striatal medium spiny neurons in HD has be an active area of research. Mutant huntingtin is expressed throughout the body, so the reason that it should preferentially lead to loss of a small subset of neurons is not obvious.
Several hypotheses regarding the preferential involvement of the striatum in the course of HD pathogenesis have emerged over the past decade. In 2001, Zuccato et al. suggested that a lack of neurotrophic support from BDNF, normally made in the cortex and transported to the striatum, is at least in part responsible for this preferential susceptibility. In 2002, Zeron et al. provided evidence for a role for NR2B-subtype NMDAR activation as a trigger for selective neuronal degeneration in HD. More recent studies (Benchoua, 2008; Chavrin, 2005) have suggested that the high expression of dopamine exacerbates mutant huntingtin toxicity in the striatum.
In this study, Subramaniam and colleagues describe a series of elegant biochemical experiments showing that a recently identified, striatally-enriched small G protein, Rhes (ras homolog enriched in the striatum), directly interacts with Huntingtin, induces SUMOylation of the mutant protein, and thereby confers mutant Huntingtin toxicity to cells expressing it. Previous studies have implicated Rhes in dopamine signaling and striatal function, with conflicting reports on the effect of Rhes knockout on locomotion in different genetic backgrounds (Errico, 2008; Spano, 2004). Their findings also suggest that Rhes might cause toxicity, partly, by preventing neurons from forming the intracellular deposits of mutant Htt called inclusion bodies. These results are consistent with previous findings indicating that inclusion body formation may serve as a protective response by neurons against more soluble and toxic forms of the protein (Arrasate et al., 2004).
The current study provides an interesting insight into the selectivity of cell death in Huntington disease. Preventing farnesylation of Rhes may be a therapeutic target to investigate, especially since farnesyl transferase inhibitors have already been developed for the clinic. The absence of drastic phenotypes in the knockouts is encouraging, if Rhes is to be pursued as a therapeutic target.
However, further studies are needed to truly establish Rhes as a striatal-specific mediator of mutant Huntington toxicity and as a therapeutic target for HD therapy. First and foremost, it will be essential to verify that Rhes mediates toxicity of mutant Huntingtin in primary neurons, in vivo, as well as in the cell line models used in this study. Will the HD phenotype be significantly reduced in a Rhes knockout background? Will ectopic expression of Rhes in primary cortical and hippocampal neurons confer the same degree of toxicity of mutant Huntington as in primary striatal neurons? Second, while Rhes is highly enriched in the striatum, its mRNA is also expressed in various other regions, notably the CA1/CA3 layers of the hippocampus, the granular layer of the cerebellum, and anterior thalamus (Vargiu 2004, Harrison 2008). Whether the Rhes protein is also expressed in these other neuronal population needs further exploration to determine whether Rhes is a truly striatal-specific factor. Third, both Rhes and dopamine are suggested to contribute to the preferential loss of striatal neurons, and Rhes is suggested to have roles in dopamine signaling in the striatum. Finally, it will be interesting to see whether Rhes can also explain the differential susceptibilities of medium spiny neurons and interneurons within the striatum, as interneurons are largely spared in HD.
As with other aspects of biology, a complex image is developing regarding the factors that regulate the preferential loss of striatal neurons in HD. Whether these anatomical and molecular regulators of toxicity, described here or yet to be discovered, act in a concerted fashion or independent of each other remains to be explored. Rhes is already suggested to have roles in dopamine signaling, and both Rhes and dopamine are suggested to contribute to the selective vulnerability of striatal neurons. How these signaling pathways are regulated and fine-tuned within a complex neural network will give us a better understanding of the pathological basis in Huntington disease.
Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S.
Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death.
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Rhes is involved in striatal function.
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Zeron MM, Hansson O, Chen N, Wellington CL, Leavitt BR, Brundin P, Hayden MR, Raymond LA.
Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease.
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Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E.
Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease.
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This paper by Subramaniam and colleagues presents some intriguing findings. For one thing, they identify the small G protein, Rhes, as defining a potential new class of non-traditional SUMO E3 ligases, thus opening a potential new window on the SUMOylation machinery. In addition, their study raises the possibility that Rhes activity may exacerbate the pathology of mutant Htt by preferentially causing its SUMOylation with consequences similar to those observed in Drosophila and cells. It will be interesting to see whether Rhes knockout mutations will suppress pathogenesis in mouse models of HD.
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