Proteomic identification of novel proteins associated with Lewy bodies.
The manifestation of Lewy bodies (LB) in the brain is a hallmark of Parkinson's disease. Here, we present a comprehensive analysis of protein elements in Lewy bodies by comparative mass spectrometry. Cortical LB inclusions were enriched by sucrose gradient centrifugation from postmortem brains, and a negative control sample was prepared from specimen without LB pathology. Whereas approximately 550 proteins were identified in the LB-enriched sample by mass spectrometry, quantitative comparison with the control sample revealed that approximately 40 proteins were co-enriched with alpha-synuclein, the major component in Lewy bodies. As expected, the list of proteins included previously reported constituents, such as those involved in protein folding, membrane trafficking and oxidative stress. More interestingly, we discovered in the LB-enriched sample several kinases (MAPKK1/MEK1, protein kinase C, and doublecortin-like kinase), a novel deubiquitinating enzyme (otubain 1), and numerous ubiquitin ligases (KPC and SCF). The proteomic studies provide enzyme candidates to investigate the regulation of alpha-synuclein and/or other LB proteins, which may contribute to the formation of Lewy bodies and the toxicity of alpha-synuclein in the related neurodegenerative disorders.
Xia
Qiangwei
Q
Department of Human Genetics, the Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Liao
Lujian
L
Cheng
Dongmei
D
Duong
Duc M
DM
Gearing
Marla
M
Lah
James J
JJ
Levey
Allan I
AI
Peng
Junmin
J
D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002102:Cadaver; D006801:Humans; D016631:Lewy Bodies / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000302:isolation & purification / Q000378:metabolism*; D011180:Postmortem Changes; D017510:Protein Folding; D011494:Protein Kinases / Q000302:isolation & purification / Q000378:metabolism; D040901:Proteomics; D051843:Synucleins / Q000302:isolation & purification / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000302:isolation & purification / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000302:isolation & purification / Q000378:metabolism
D009419:Nerve Tissue Proteins; D051843:Synucleins; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; D044764:Ubiquitin-Activating Enzymes