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J. Biol. Chem., Vol. 282, Issue 34, 24554-24562, August 24, 2007

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Loss of Huntingtin Function Complemented by Small Molecules Acting as Repressor Element 1/Neuron Restrictive Silencer Element Silencer Modulators^*

Dorotea Rigamonti¹, Daniele Bolognini¹, Cesare Mutti¹, Chiara Zuccato, Marzia Tartari², Francesco Sola^¶, Marta Valenza², Aleksey G. Kazantsev^||, and Elena Cattaneo³

From the Centre for Stem Cell Research and Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, Milan 20133, Italy, the Dialectica S.r.l., c/o Nerviano Medical Sciences, V.le Pasteur 10, Nerviano MI 20014, Italy, the ^¶Biology Department, Nerviano Medical Sciences S.r.l., Building 75A, V.le Pasteur 10, Nerviano MI 20014, Italy, and the ^||MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, Massachusetts 02129-4404

Increased levels of the repressor element 1/neuron restrictive silencer element (RE1/NRSE) silencing activity promoter, and a consequent reduction in the transcription of many RE1/NRSE-bearing neuronal genes, including brain-derived neurotrophic factor (BDNF), have been demonstrated in Huntington disease (HD) and represent one possible effector of its selective neuronal vulnerability. Restoring the expression levels of neuronal genes in diseased neurons therefore seems to be an attractive therapeutic approach. To this end, we have developed a cell-based reporter assay for monitoring RE1/NRSE silencing activity and validated it by genetically inactivating the RE1/NRSE or pharmacologically stimulating global transcription. In a pilot compound screen, we identified three closely related structural analogues that up-regulate reporter expression at low nanomolar concentrations, and follow-up studies have shown that they efficaciously increase endogenous BDNF levels in HD cells. Moreover, one of the compounds increases the viability of HD cells. Our findings suggest a new avenue for the development of drugs for HD and other neurodegenerative disorders based on the pharmacological up-regulation of the production of the neuronal survival factor BDNF and of other RE1/NRSE-regulated neuronal genes.

Received for publication, October 20, 2006 , and in revised form, May 31, 2007.

^* This work was supported by Telethon-Italy, the Fondo Incentivazione Ricerca di Base (Ministero dell' Istruzione, Universita e Ricera, Italy), the Fondazione Cariplo (Italy), and NeuroNE (FP6, European Union). M. T. and M. V. are competing interests: E. C. and D. R. hold equity in Dialectica S.r.l., a recent spin-off company of the University of Milan, which holds the patent application: "Method for the identification of drugs useful in Huntington's Disease therapy," Inventors: Cattaneo, E., Zuccato, C. (Universita' di Milano) (Italy, No. MI2002A000809; Europe, No. 03712609.1; and U. S. A., No. 511 665). Dialectica S.r.l. has more recently filed a patent application concerning the use of the compounds related to this study. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Present address: Dialectica S.r.l., c/o Nerviano Medical Sciences, V.le Pasteur 10, Nerviano MI 20014, Italy.

² Supported by Sovvenzione Globale INGENIO: European Social Fund, Minister of Work and Social previdence, Lombardy Region.

³ To whom correspondence should be addressed. Tel.: 39-02-5031-8333; Fax: 39-02-5031-8284; E-mail: elena.cattaneo{at}unimi.it.

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