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Vol. 14, Issue 11, 4541-4556, November 2003

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Inhibition of Proteasomal Activity Causes Inclusion Formation in Neuronal and Non-Neuronal Cells Overexpressing Parkin

Helen C. Ardley ^* , Gina B. Scott ^*, Stephen A. Rose ^*, Nancy G. S. Tan ^* , Alexander F. Markham ^*, and Philip A. Robinson ^* 

^* Molecular Medicine Unit, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, United Kingdom; Leeds Dental Institute, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, United Kingdom

Submitted February 11, 2003; Revised June 23, 2003; Accepted July 24, 2003
Monitoring Editor: Pamela Silver

Association between protein inclusions and neurodegenerative diseases, including Parkinson's and Alzheimer's diseases, and polyglutamine disorders, has been widely documented. Although ubiquitin is conjugated to many of these aggregated proteins, the 26S proteasome does not efficiently degrade them. Mutations in the ubiquitin-protein ligase Parkin are associated with autosomal recessive juvenile Parkinsonism. Although Parkin-positive inclusions are not detected in brains of autosomal recessive juvenile Parkinsonism patients, Parkin is found in Lewy bodies in sporadic disease. This suggests that loss of Parkin ligase activity via mutation, or sequestration to Lewy bodies, is a contributory factor to sporadic disease onset. We now demonstrate that decreased proteasomal activity causes formation of large, noncytotoxic inclusions within the cytoplasm of both neuronal and nonneuronal cells overexpressing Parkin. This is not a general phenomenon as there is an absence of similar inclusions when HHARI, a structural homolog of Parkin, is overexpressed. The inclusions colocalize with ubiquitin and with proteasomes. Furthermore, Parkin inclusions colocalize with -tubulin, acetylated -tubulin, and cause redistribution of vimentin, suggesting aggresome-like properties. Our data imply that lower proteasomal activity, previously observed in brain tissue of Parkinson's disease patients, leads to Parkin accumulation and a concomitant reduction in ligase activity, thereby promoting Lewy body formation.

Present address: Cancer Research Initiative Foundation, Subang Jaya Medical Centre, No 1, Jalan SS12/1A, 47500 Subang Jaya, Selangor, Malaysia.

Corresponding author. E-mail address: h.c.ardley{at}leeds.ac.uk.

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