Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies

Michael G. Schlossmacher*, Matthew P. Frosch, Wei Ping Gai, Miguel Medina, Nutan Sharma, Lysia Forno, Tomoyo Ochiishi, Hideki Shimura, Ronit Sharon, Nobutaka Hattori, J. William Langston, Yoshikuni Mizuno, Bradley T. Hyman, Dennis J. Selkoe, Kenneth S. Kosik

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

287 Scopus citations

Abstract

Mutations in α-synuclein (αS) and parkin cause heritable forms of Parkinson disease (PD). We hypothesized that neuronal parkin, a known E3 ubiquitin ligase, facilitates the formation of Lewy bodies (LBs), a pathological hallmark of PD. Here, we report that affinity-purified parkin antibodies labeled classical LBs in substantia nigra sections from four related human disorders: sporadic PD, inherited αs-linked PD, dementia with LBs (DLB), and LB-positive, parkin-linked PD. Anti-parkin antibodies also detected LBs in entorhinal and cingulate cortices from DLB brain and αS inclusions in sympathetic gangliocytes from sporadic PD. Double labeling with confocal microscopy of DLB midbrain sections revealed that ∼90% of anti-αS-reactive LBs were also detected by a parkin antibody to amino acids 342 to 353. Accordingly, parkin proteins, including the 53-kd mature lsoform, were present in affinity-isolated LBs from DLB cortex. Fluorescence resonance energy transfer and immunoelectron microscopy showed that αS and parkin co-localized within brainstem and cortical LBs. Biochemically, parkin appeared most enriched in cytosolic and postsynaptic fractions of adult rat brain, but also in purified, αS-rich presynaptic elements that additionally contained parkin's E2-binding partner, UbcH7. We conclude that parkin and UbcH7 are present with αS in subcellular compartments of normal brain and that parkin frequently co-localizes with αS aggregates in the characteristic LB inclusions of PD and DLB. These results suggest that functional parkin proteins may be required during LB formation.

Original languageAmerican English
Pages (from-to)1655-1667
Number of pages13
JournalAmerican Journal of Pathology
Volume160
Issue number5
DOIs
StatePublished - 2002
Externally publishedYes

Bibliographical note

Funding Information:
Supported by grants from the Lefler Foundation, the Grass Foundation, the National Institutes of Health (NS02127 to M. G. S.), the P. Beeson Award (to M. P. F.), the National Health & Medical Research Council of Australia (to W. P. G.), the Veterans’ Administration Medical Research Program (to L. F.), and the Morris R. Udall Centers (NS38372 to B. T. H. and NS38375 to M. P. F., D. J. S., and K. S. K.).

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