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From the Departments of Neurology*and Pathology,Center for Neurologic Diseases, Brigham and Women’s Hospital, Boston, Massachusetts; the Department of Neurology,Alzheimer’s Disease Research Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; the Department of Physiology and Centre for Neuroscience,Flinders University, Bedford Park, Australia; the Palo Alto Veterans Administration Health Care System,¶Palo Alto, California; the Parkinson’s Institute,**Sunnyvale, California; and the Department of Neurology,||Juntendo University Medical School, Tokyo, Japan
Mutations in 
-synuclein (S) 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 S-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 S inclusions in sympathetic gangliocytes from sporadic PD. Double labeling with confocal microscopy of DLB midbrain sections revealed that 
90% of anti-S-reactive LBs were also detected by a parkin antibody to amino acids 342 to 353. Accordingly, parkin proteins, including the 53-kd mature isoform, were present in affinity-isolated LBs from DLB cortex. Fluorescence resonance energy transfer and immunoelectron microscopy showed that S 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, S-rich presynaptic elements that additionally contained parkin’s E2-binding partner, UbcH7. We conclude that parkin and UbcH7 are present with S in subcellular compartments of normal brain and that parkin frequently co-localizes with S aggregates in the characteristic LB inclusions of PD and DLB. These results suggest that functional parkin proteins may be required during LB formation.
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 N. Hishikawa, J.-i. Niwa, M. Doyu, T. Ito, S. Ishigaki, Y. Hashizume, and G. Sobue Dorfin Localizes to the Ubiquitylated Inclusions in Parkinson's Disease, Dementia with Lewy Bodies, Multiple System Atrophy, and Amyotrophic Lateral Sclerosis Am. J. Pathol., August 1, 2003; 163(2): 609 - 619. [Abstract] [Full Text] [PDF]
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M. C. J. Dekker, V. Bonifati, and C. M. van Duijn Parkinson's disease: piecing together a genetic jigsaw Brain, August 1, 2003; 126(8): 1722 - 1733. [Abstract] [Full Text] [PDF]
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T. Ito, J.-i. Niwa, N. Hishikawa, S. Ishigaki, M. Doyu, and G. Sobue Dorfin Localizes to Lewy Bodies and Ubiquitylates Synphilin-1 J. Biol. Chem., August 1, 2003; 278(31): 29106 - 29114. [Abstract] [Full Text] [PDF]
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S. Kahns, M. Kalai, L. D. Jakobsen, B. F. C. Clark, P. Vandenabeele, and P. H. Jensen Caspase-1 and Caspase-8 Cleave and Inactivate Cellular Parkin J. Biol. Chem., June 20, 2003; 278(26): 23376 - 23380. [Abstract] [Full Text] [PDF]
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M. Ihara, H. Tomimoto, H. Kitayama, Y. Morioka, I. Akiguchi, H. Shibasaki, M. Noda, and M. Kinoshita Association of the Cytoskeletal GTP-binding Protein Sept4/H5 with Cytoplasmic Inclusions Found in Parkinson's Disease and Other Synucleinopathies J. Biol. Chem., June 20, 2003; 278(26): 24095 - 24102. [Abstract] [Full Text] [PDF]
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O. Corti, C. Hampe, H. Koutnikova, F. Darios, S. Jacquier, A. Prigent, J.-C. Robinson, L. Pradier, M. Ruberg, M. Mirande, et al. The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration Hum. Mol. Genet., June 15, 2003; 12(12): 1427 - 1437. [Abstract] [Full Text] [PDF]
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Y. C. Tsai, P. S. Fishman, N. V. Thakor, and G. A. Oyler Parkin Facilitates the Elimination of Expanded Polyglutamine Proteins and Leads to Preservation of Proteasome Function J. Biol. Chem., June 6, 2003; 278(24): 22044 - 22055. [Abstract] [Full Text] [PDF]
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H. Snyder, K. Mensah, C. Theisler, J. Lee, A. Matouschek, and B. Wolozin Aggregated and Monomeric alpha -Synuclein Bind to the S6' Proteasomal Protein and Inhibit Proteasomal Function J. Biol. Chem., March 28, 2003; 278(14): 11753 - 11759. [Abstract] [Full Text] [PDF]
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E. Junn, S. S. Lee, U. T. Suhr, and M. M. Mouradian Parkin Accumulation in Aggresomes Due to Proteasome Impairment J. Biol. Chem., November 27, 2002; 277(49): 47870 - 47877. [Abstract] [Full Text] [PDF]
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K. Steece-Collier, E. Maries, and J. H. Kordower Etiology of Parkinson's disease: Genetics and environment revisited PNAS, October 29, 2002; 99(22): 13972 - 13974. [Full Text] [PDF]
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