Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 324 (5932): 1327-1330

Copyright © 2009 by the American Association for the Advancement of Science

Rhes, a Striatal Specific Protein, Mediates Mutant-Huntingtin Cytotoxicity

Srinivasa Subramaniam, Katherine M. Sixt, Roxanne Barrow, Solomon H. Snyder*

Abstract: Huntington’s disease (HD) is caused by a polyglutamine repeat in the protein huntingtin (Htt) with mutant Htt (mHtt) expressed throughout the body and similarly in all brain regions. Yet, HD neuropathology is largely restricted to the corpus striatum. We report that the small guanine nucleotide–binding protein Rhes, which is localized very selectively to the striatum, binds physiologically to mHtt. Using cultured cells, we found Rhes induces sumoylation of mHtt, which leads to cytotoxicity. Thus, Rhes-mHtt interactions can account for the localized neuropathology of HD.

The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.

* To whom correspondence should be addressed. E-mail: ssnyder{at}jhmi.edu


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Activators of G Protein Signaling Exhibit Broad Functionality and Define a Distinct Core Signaling Triad.
J. B. Blumer and S. M. Lanier (2014)
Mol. Pharmacol. 85, 388-396
   Abstract »    Full Text »    PDF »
Rheb GTPase Regulates {beta}-Secretase Levels and Amyloid {beta} Generation.
N. Shahani, W. Pryor, S. Swarnkar, N. Kholodilov, G. Thinakaran, R. E. Burke, and S. Subramaniam (2014)
J. Biol. Chem. 289, 5799-5808
   Abstract »    Full Text »    PDF »
Rhes, a Striatal-selective Protein Implicated in Huntington Disease, Binds Beclin-1 and Activates Autophagy.
R. G. Mealer, A. J. Murray, N. Shahani, S. Subramaniam, and S. H. Snyder (2014)
J. Biol. Chem. 289, 3547-3554
   Abstract »    Full Text »    PDF »
Advances in Huntington Disease Drug Discovery: Novel Approaches to Model Disease Phenotypes.
J. Bard, M. D. Wall, O. Lazari, J. Arjomand, and I. Munoz-Sanjuan (2014)
J Biomol Screen 19, 191-204
   Abstract »    Full Text »    PDF »
The Regulation of Autophagosome Dynamics by Huntingtin and HAP1 Is Disrupted by Expression of Mutant Huntingtin, Leading to Defective Cargo Degradation.
Y. C. Wong and E. L. F. Holzbaur (2014)
J. Neurosci. 34, 1293-1305
   Abstract »    Full Text »    PDF »
A novel human embryonic stem cell-derived Huntington's disease neuronal model exhibits mutant huntingtin (mHTT) aggregates and soluble mHTT-dependent neurodegeneration.
B. Lu and J. Palacino (2013)
FASEB J 27, 1820-1829
   Abstract »    Full Text »    PDF »
Rhes Deletion Is Neuroprotective in the 3-Nitropropionic Acid Model of Huntington's Disease.
R. G. Mealer, S. Subramaniam, and S. H. Snyder (2013)
J. Neurosci. 33, 4206-4210
   Abstract »    Full Text »    PDF »
Dexras1, a Small GTPase, Is Required for Glutamate-NMDA Neurotoxicity.
Y. Chen, R. S. Khan, A. Cwanger, Y. Song, C. Steenstra, S. Bang, J. H. Cheah, J. Dunaief, K. S. Shindler, S. H. Snyder, et al. (2013)
J. Neurosci. 33, 3582-3587
   Abstract »    Full Text »    PDF »
PGC-1{alpha} Negatively Regulates Extrasynaptic NMDAR Activity and Excitotoxicity.
C. Puddifoot, M.-A. Martel, F. X. Soriano, A. Camacho, A. Vidal-Puig, D. J. A. Wyllie, and G. E. Hardingham (2012)
J. Neurosci. 32, 6995-7000
   Abstract »    Full Text »    PDF »
Small Changes, Big Impact: Posttranslational Modifications and Function of Huntingtin in Huntington Disease.
D. E. Ehrnhoefer, L. Sutton, and M. R. Hayden (2011)
Neuroscientist 17, 475-492
   Abstract »    PDF »
Neuron-specific proteotoxicity of mutant ataxin-3 in C. elegans: rescue by the DAF-16 and HSF-1 pathways.
A. Teixeira-Castro, M. Ailion, A. Jalles, H. R. Brignull, J. L. Vilaca, N. Dias, P. Rodrigues, J. F. Oliveira, A. Neves-Carvalho, R. I. Morimoto, et al. (2011)
Hum. Mol. Genet. 20, 2996-3009
   Abstract »    Full Text »    PDF »
Huntingtin affinity for partners is not changed by polyglutamine length: aggregation itself triggers aberrant interactions.
A. Davranche, H. Aviolat, G. Zeder-Lutz, D. Busso, D. Altschuh, Y. Trottier, and F. A. C. Klein (2011)
Hum. Mol. Genet. 20, 2795-2806
   Abstract »    Full Text »    PDF »
Hsa-miR-34b is a plasma-stable microRNA that is elevated in pre-manifest Huntington's disease.
P. M. Gaughwin, M. Ciesla, N. Lahiri, S. J. Tabrizi, P. Brundin, and M. Bjorkqvist (2011)
Hum. Mol. Genet. 20, 2225-2237
   Abstract »    Full Text »    PDF »
Huntington's Disease.
S. Finkbeiner (2011)
Cold Spring Harb Perspect Biol 3, a007476
   Abstract »    Full Text »    PDF »
Expression of Huntington's disease protein results in apoptotic neurons in the brains of cloned transgenic pigs.
D. Yang, C.-E. Wang, B. Zhao, W. Li, Z. Ouyang, Z. Liu, H. Yang, P. Fan, A. O'Neill, W. Gu, et al. (2010)
Hum. Mol. Genet. 19, 3983-3994
   Abstract »    Full Text »    PDF »
Polyglutamine Diseases: Where does Toxicity Come from? What is Toxicity? Where are We Going?.
T. Takahashi, S. Katada, and O. Onodera (2010)
J Mol Cell Biol 2, 180-191
   Abstract »    Full Text »    PDF »
Rhes, a Physiologic Regulator of Sumoylation, Enhances Cross-sumoylation between the Basic Sumoylation Enzymes E1 and Ubc9.
S. Subramaniam, R. G. Mealer, K. M. Sixt, R. K. Barrow, A. Usiello, and S. H. Snyder (2010)
J. Biol. Chem. 285, 20428-20432
   Abstract »    Full Text »    PDF »
Molecular Mechanisms and Potential Therapeutical Targets in Huntington's Disease.
C. Zuccato, M. Valenza, and E. Cattaneo (2010)
Physiol Rev 90, 905-981
   Abstract »    Full Text »    PDF »
Differential Effects of Sumoylation on Transcription and Alternative Splicing by Transcription Elongation Regulator 1 (TCERG1).
M. Sanchez-Alvarez, M. Montes, N. Sanchez-Hernandez, C. Hernandez-Munain, and C. Sune (2010)
J. Biol. Chem. 285, 15220-15233
   Abstract »    Full Text »    PDF »
SUMOylation attenuates the aggregation propensity and cellular toxicity of the polyglutamine expanded ataxin-7.
A. Janer, A. Werner, J. Takahashi-Fujigasaki, A. Daret, H. Fujigasaki, K. Takada, C. Duyckaerts, A. Brice, A. Dejean, and A. Sittler (2010)
Hum. Mol. Genet. 19, 181-195
   Abstract »    Full Text »    PDF »
Detection, Validation, and Downstream Analysis of Allelic Variation in Gene Expression.
D. C. Ciobanu, L. Lu, K. Mozhui, X. Wang, M. Jagalur, J. A. Morris, W. L. Taylor, K. Dietz, P. Simon, and R. W. Williams (2010)
Genetics 184, 119-128
   Abstract »    Full Text »    PDF »
SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple nonconsensus sites within the B domain and is linked to its activity cycle.
C. Figueroa-Romero, J. A. Iniguez-Lluhi, J. Stadler, C.-R. Chang, D. Arnoult, P. J. Keller, Y. Hong, C. Blackstone, and E. L. Feldman (2009)
FASEB J 23, 3917-3927
   Abstract »    Full Text »    PDF »
Science Signaling Podcast: 21 July 2009.
W. Wong and A. M. VanHook (2009)
Science Signaling 2, pc13
   Abstract »    Full Text »
Previously Unknown Protein Contributes to Huntington Disease.
(2009)
Journal Watch (General) 2009, 5
   Full Text »
Previously Unknown Protein Contributes to Huntington Disease.
Anthony L. Komaroff, MD and Anthony L. Komaroff, MD (2009)
Journal Watch 2009, JW200906300000005
   Full Text »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882