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J. Biol. Chem., Vol. 280, Issue 14, 13735-13741, April 8, 2005

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Latent S49P Neuroserpin Forms Polymers in the Dementia Familial Encephalopathy with Neuroserpin Inclusion Bodies^*

Maki Onda¶, Didier Belorgey, Lynda K. Sharp, and David A. Lomas

From the Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, United Kingdom and the Department of Environmental Sciences, Faculty of Science, Osaka Women's University, Daisen-cho 2-1, Sakai 590-0035, Japan

The serpinopathies result from conformational transitions in members of the serine proteinase inhibitor superfamily with aberrant tissue deposition or loss of function. They are typified by mutants of neuroserpin that are retained within the endoplasmic reticulum of neurons as ordered polymers in association with dementia. We show here that the S49P mutant of neuroserpin that causes the dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB) forms a latent species in vitro and in vivo in addition to the formation of polymers. Latent neuroserpin is thermostable and inactive as a proteinase inhibitor, but activity can be restored by refolding. Strikingly, latent S49P neuroserpin is unlike any other latent serine proteinase inhibitor (serpin) in that it spontaneously forms polymers under physiological conditions. These data provide an alternative method for the inactivation of mutant neuroserpin as a proteinase inhibitor in FENIB and demonstrate a second pathway for the formation of intracellular polymers in association with disease.

Received for publication, November 24, 2004 , and in revised form, January 18, 2005.

^* This work was supported by the Medical Research Council (UK), the Wellcome Trust (UK), and the Papworth National Health Service Trust. 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.

^¶ To whom correspondence should be addressed. Tel.: 81-72-222-4811; Fax: 81-72-222-4791; E-mail: onda{at}center.osaka-wu.ac.jp.

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