Document Detail


Leucine-rich repeat kinase 2 expression leads to aggresome formation that is not associated with alpha-synuclein inclusions.
MedLine Citation:
PMID:  19535993     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mutations in leucine-rich repeat kinase-2 (LRRK2) are the most common known cause of Parkinson disease, but how this protein results in the pathobiology of Parkinson disease is unknown. Moreover, there is variability in pathology among cases, and alpha-synuclein (alpha-syn) neuronal inclusions are often present, but whether LRRK2 is present in these pathological inclusions is controversial. This study characterizes novel LRRK2 antibodies, some of which preferentially recognize an aggregated form of LRRK2, as observed in cell culture models. Large perinuclear aggregates containing LRRK2 were promoted by proteasome inhibition and prevented by microtubule polymerization inhibition. Furthermore, they were vimentin- and gamma-tubulin- but not lamp1-immunoreactive, suggesting that these structures fit the definition of aggresomes. Inhibition of heat shock protein 90 led to the degradation of only the soluble/cytosolic pool of LRRK2, suggesting that the aggresomes formed independent of the stability provided by the heat shock protein 90. Although these novel anti-LRRK2 antibodies identified aggregates in model cell systems, they did not immunostain pathological inclusions in human brains. Furthermore, coexpression of LRRK2 and alpha-syn did not recruit alpha-syn into aggresomes in cultured cells, even in the presence of proteasome inhibition. Thus, although LRRK2 is a model system for aggresome formation, LRRK2 is not present in alpha-syn pathological inclusions.
Authors:
Elisa A Waxman; Jason P Covy; Irene Bukh; Xiaojie Li; Ted M Dawson; Benoit I Giasson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of neuropathology and experimental neurology     Volume:  68     ISSN:  0022-3069     ISO Abbreviation:  J. Neuropathol. Exp. Neurol.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-06-30     Completed Date:  2009-08-10     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  2985192R     Medline TA:  J Neuropathol Exp Neurol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  785-96     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Aged
Aged, 80 and over
Animals
Antibodies / immunology
Brain / metabolism,  pathology*
COS Cells
Cell Line
Cercopithecus aethiops
Female
HSP90 Heat-Shock Proteins / metabolism
Humans
Inclusion Bodies / immunology,  metabolism*
Lewy Body Disease / immunology,  metabolism,  pathology
Male
Middle Aged
Multiple System Atrophy / immunology,  metabolism,  pathology
Neurodegenerative Diseases / immunology,  metabolism,  pathology
Parkinson Disease / immunology,  metabolism,  pathology
Protein-Serine-Threonine Kinases / genetics,  immunology,  metabolism*
alpha-Synuclein / metabolism*
Grant Support
ID/Acronym/Agency:
AG09215/AG/NIA NIH HHS; NS053488/NS/NINDS NIH HHS; NS38377/NS/NINDS NIH HHS; P01 AG009215/AG/NIA NIH HHS; P01 AG009215-180009/AG/NIA NIH HHS; P01 AG009215-190009/AG/NIA NIH HHS; P01 AG009215-200009/AG/NIA NIH HHS; P50 NS038377/NS/NINDS NIH HHS; P50 NS038377-10/NS/NINDS NIH HHS; P50 NS053488/NS/NINDS NIH HHS; P50 NS053488-020004/NS/NINDS NIH HHS; P50 NS053488-030004/NS/NINDS NIH HHS; T32 AG000255/AG/NIA NIH HHS; T32 AG000255-10/AG/NIA NIH HHS; T32 AG000255-12/AG/NIA NIH HHS; T32 AG00255/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Antibodies; 0/HSP90 Heat-Shock Proteins; 0/alpha-Synuclein; EC 2.7.11.1/LRRK2 protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases
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