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J. Biol. Chem., Vol. 278, Issue 48, 48120-48128, November 28, 2003

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Novel Monoclonal Antibodies Demonstrate Biochemical Variation of Brain Parkin with Age^*

Aaron C. Pawlyk¶, Benoit I. Giasson||, Deepak M. Sampathu¶, Francisco A. Perez**, Kah Leong Lim, Valina L. Dawson, Ted M. Dawson, Richard D. Palmiter**, John Q. Trojanowski¶¶, and Virginia M.-Y. Lee||||

From the Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, and ^¶¶Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, the ^**Department of Biochemistry, University of Washington, Seattle, Washington 98195, Neurodegeneration Research Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore, and the Departments of Neurology and Neuroscience, The Johns Hopkins University, Baltimore, Maryland 21287

Autosomal recessive juvenile parkinsonism is a movement disorder associated with the degeneration of dopaminergic neurons in substantia nigra pars compacta. The loss of functional parkin caused by parkin gene mutations is the most common single cause of juvenile parkinsonism. Parkin has been shown to aid in protecting cells from endoplasmic reticulum and oxidative stressors presumably due to ubiquitin ligase activity of parkin that targets proteins for proteasomal degradation. However, studies on parkin have been impeded because of limited reagents specific for this protein. Here we report the generation and characterization of a panel of parkin-specific monoclonal antibodies. Biochemical analyses indicate that parkin is present only in the high salt-extractable fraction of mouse brain, whereas it is present in both the high salt-extractable and RIPA-resistant, SDS-extractable fraction in young human brain. Parkin is present at decreased levels in the high salt-extractable fraction and at increased levels in the SDS-extractable fraction from aged human brain. This shift in the extractability of parkin upon aging is seen in humans but not in mice, demonstrating species-specific differences in the biochemical characteristics of murine versus human parkin. Finally, by using these highly specific anti-parkin monoclonal antibodies, it was not possible to detect parkin in -synuclein-containing lesions in -synucleinopathies, thereby challenging prior inferences about the role of parkin in movement disorders other than autosomal recessive juvenile parkinsonism.

Received for publication, June 27, 2003 , and in revised form, September 3, 2003.

^* This work was supported in part by NIA and NINDS grants from the National Institutes of Health and the Michael J. Fox Foundation. 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.

Both authors contributed equally to this work.

^¶ Supported by a National Institutes of Health training grant (Training in Age-related Neurodegenerative Diseases).

^|| Supported by a fellowship from the Canadian Institutes of Health Research.

^|||| The John H. Ware III Chair of Alzheimer's Research. To whom correspondence should be addressed. Tel.: 215-662-6427; E-mail: vmylee{at}mail.med.upenn.edu.

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