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(American Journal of Pathology. 2003;163:91-100.)
© 2003 American Society for Investigative Pathology

Ubiquitination of -Synuclein Is Not Required for Formation of Pathological Inclusions in -Synucleinopathies

Deepak M. Sampathu^*, Benoit I. Giasson^*, Aaron C. Pawlyk^*, John Q. Trojanowski^* and Virginia M.-Y. Lee^*

From the Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine,^* and the Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

-Synucleinopathies, including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, are neurodegenerative disorders in which abnormal inclusions containing -synuclein accumulate in selectively vulnerable neurons and glia. In this report, immunohistochemistry demonstrates ubiquitin in subsets of -synuclein inclusions in dementia with Lewy bodies and multiple system atrophy. Biochemistry demonstrates that -synuclein in the sodium dodecyl sulfate-soluble fractions of diseased brains is ubiquitinated, with mono- and di-ubiquitinated species predominating over polyubiquitinated forms. Similar immunohistochemical and biochemical characteristics were observed in an A53T mutant human -synuclein transgenic mouse model of neurodegenerative -synucleinopathies. Furthermore, in vitro ubiquitination of -synuclein fibrils recapitulated the pattern of -synuclein ubiquitination observed in human disease and the A53T -synuclein mouse model. These results suggest that ubiquitination of -synuclein is not required for inclusion formation and follows the fibrillization of -synuclein.

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