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J. Biol. Chem., Vol. 283, Issue 10, 6330-6336, March 7, 2008

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Noninvasive Measurement of Protein Aggregation by Mutant Huntingtin Fragments or -Synuclein in the Lens^*

Paul J. Muchowski¹, Richard Ramsden, QuangVu Nguyen, Ernest E. Arnett, Teri M. Greiling, Susan K. Anderson, and John I. Clark^¶2

From the Departments of Pharmacology, Biological Structure, and ^¶Ophthalmology, University of Washington, Seattle, Washington 98195

Many diverse human diseases are associated with protein aggregation in ordered fibrillar structures called amyloid. Amyloid formation may mediate aberrant protein interactions that culminate in neurodegeneration in Alzheimer, Huntington, and Parkinson diseases and in prion encephalopathies. Studies of protein aggregation in the brain are hampered by limitations in imaging techniques and often require invasive methods that can only be performed postmortem. Here we describe transgenic mice in which aggregation-prone proteins that cause Huntington and Parkinson disease are expressed in the ocular lens. Expression of a mutant huntingtin fragment or -synuclein in the lens leads to protein aggregation and cataract formation, which can be monitored in real time by noninvasive, highly sensitive optical techniques. Expression of a mutant huntingtin fragment in mice lacking the major lens chaperone, B-crystallin, markedly accelerated the onset and severity of aggregation, demonstrating that the endogenous chaperone activity of B-crystallin suppresses aggregation in vivo. These novel mouse models will facilitate the characterization of protein aggregation in vivo and are being used in efficient and economical screens for chemical and genetic modifiers of disease-relevant protein aggregation.

Received for publication, November 27, 2007 , and in revised form, December 24, 2007.

^* This study was supported by grants from the Hereditary Disease Foundation under the auspices of the "Cure Huntington's Disease Initiative," the HighQ Foundation, and the Nathan Shock Center of Excellence in the Basic Biology of Aging and from the Royalty Research Fund at the University of Washington (to P. J. M.) and by Grant EY04552 from the National Eye Institute (to J. I. C.) and a grant from the Royalty Research Fund from the University of Washington (to P. J. M.). 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.

² Supported by the U. S. National Eye Institute.

¹ To whom correspondence should be addressed. Gladstone Institute of Neurological Disease, Dept. of Biochemistry and Biophysics, and Dept. of Neurology, University of California, San Francisco, California, 94158. Tel.: 415-734-2515; Fax: 415-355-0824; E-mail: pmuchowski{at}gladstone.ucsf.edu.

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