title: Leucine-rich repeat kinase 2 expression leads to aggresome formation that is not associated with alpha-synuclein inclusions.
abstract: 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.affiliation: Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6084, USA.
authors.forename: Elisa A
authors.initials: EA
authors.lastname: Waxman
authors.forename: Jason P
authors.initials: JP
authors.lastname: Covy
authors.forename: Irene
authors.initials: I
authors.lastname: Bukh
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Li
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.forename: Benoit I
authors.initials: BI
authors.lastname: Giasson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000276:immunology / Q000378:metabolism*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D020961:Lewy Body Disease / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D000906:Antibodies; D018841:HSP90 Heat-Shock Proteins; D051844:alpha-Synuclein; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases