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J. Biol. Chem., Vol. 283, Issue 10, 6489-6500, March 7, 2008

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RNA-binding Protein TLS Is a Major Nuclear Aggregate-interacting Protein in Huntingtin Exon 1 with Expanded Polyglutamine-expressing Cells^*

Hiroshi Doi, Kazumasa Okamura, Peter O. Bauer, Yoshiaki Furukawa, Hideaki Shimizu, Masaru Kurosawa, Yoko Machida, Haruko Miyazaki, Kenichi Mitsui^¶, Yoshiyuki Kuroiwa, and Nobuyuki Nukina¹

From the Laboratory for Structural Neuropathology and the ^¶Reseach Resource Center, RIKEN Brain Science Institute, 2-1 Hirosawa Wako-shi, Saitama, 351-0198, Japan and the Department of Neurology, Graduate School of Medicine, Yokohama City University, 3-1, Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan

Formation of intracellular aggregates is the hallmark of polyglutamine (polyQ) diseases. We analyzed the components of purified nuclear polyQ aggregates by mass spectrometry. As a result, we found that the RNA-binding protein translocated in liposarcoma (TLS) was one of the major components of nuclear polyQ aggregate-interacting proteins in a Huntington disease cell model and was also associated with neuronal intranuclear inclusions of R6/2 mice. In vitro study revealed that TLS could directly bind to truncated N-terminal huntingtin (tNhtt) aggregates but could not bind to monomer GST-tNhtt with 18, 42, or 62Q, indicating that the tNhtt protein acquired the ability to sequester TLS after forming aggregates. Thioflavin T assay and electron microscopic study further supported the idea that TLS bound to tNhtt-42Q aggregates at the early stage of tNhtt-42Q amyloid formation. Immunohistochemistry showed that TLS was associated with neuronal intranuclear inclusions of Huntington disease human brain. Because TLS has a variety of functional roles, the sequestration of TLS to polyQ aggregates may play a role in diverse pathological changes in the brains of patients with polyQ diseases.

Received for publication, June 28, 2007 , and in revised form, December 27, 2007.

^* This work was supported in part by grants-in-aid from the Ministry of Health, Labor and Welfare and the Ministry of Education, Culture, Sports, Science and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 2-1 Hirosawa Wako-shi, Saitama, 351-0198, Japan. Fax: 8148-462-4796; E-mail: nukina{at}brain.riken.jp.

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