Leucine-rich repeat kinase 2 expression leads to aggresome formation that is not associated with α-synuclein inclusions

Elisa A. Waxman, Jason P. Covy, Irene Bukh, Xiaojie Li, Ted M Dawson, Benoit I. Giasson

Research output: Contribution to journalArticle

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 α-synuclein (α-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 γ-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 α-syn did not recruit α-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 α-syn pathological inclusions.

Original languageEnglish (US)
Pages (from-to)785-796
Number of pages12
JournalJournal of Neuropathology and Experimental Neurology
Volume68
Issue number7
DOIs
StatePublished - Jul 2009

Fingerprint

Synucleins
Leucine
Phosphotransferases
HSP90 Heat-Shock Proteins
Proteasome Endopeptidase Complex
Parkinson Disease
Antibodies
Vimentin
Tubulin
Microtubules
Polymerization
Cultured Cells
Cell Culture Techniques

Keywords

  • α-Synuclein
  • Aggregation
  • Aggresome
  • Antibody
  • LRRK2
  • Parkinson disease

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Leucine-rich repeat kinase 2 expression leads to aggresome formation that is not associated with α-synuclein inclusions. / Waxman, Elisa A.; Covy, Jason P.; Bukh, Irene; Li, Xiaojie; Dawson, Ted M; Giasson, Benoit I.

In: Journal of Neuropathology and Experimental Neurology, Vol. 68, No. 7, 07.2009, p. 785-796.

Research output: Contribution to journalArticle

Waxman, Elisa A. ; Covy, Jason P. ; Bukh, Irene ; Li, Xiaojie ; Dawson, Ted M ; Giasson, Benoit I. / Leucine-rich repeat kinase 2 expression leads to aggresome formation that is not associated with α-synuclein inclusions. In: Journal of Neuropathology and Experimental Neurology. 2009 ; Vol. 68, No. 7. pp. 785-796.
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