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Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats.

Publication ,  Journal Article
Daher, JPL; Volpicelli-Daley, LA; Blackburn, JP; Moehle, MS; West, AB
Published in: Proc Natl Acad Sci U S A
June 24, 2014

Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene can cause late-onset Parkinson disease. Past studies have provided conflicting evidence for the protective effects of LRRK2 knockdown in models of Parkinson disease as well as other disorders. These discrepancies may be caused by uncertainty in the pathobiological mechanisms of LRRK2 action. Previously, we found that LRRK2 knockdown inhibited proinflammatory responses from cultured microglia cells. Here, we report LRRK2 knockout rats as resistant to dopaminergic neurodegeneration elicited by intracranial administration of LPS. Such resistance to dopaminergic neurodegeneration correlated with reduced proinflammatory myeloid cells recruited in the brain. Additionally, adeno-associated virus-mediated transduction of human α-synuclein also resulted in dopaminergic neurodegeneration in wild-type rats. In contrast, LRRK2 knockout animals had no significant loss of neurons and had reduced numbers of activated myeloid cells in the substantia nigra. Although LRRK2 expression in the wild-type rat midbrain remained undetected under nonpathological conditions, LRRK2 became highly expressed in inducible nitric oxide synthase (iNOS)-positive myeloid cells in the substantia nigra in response to α-synuclein overexpression or LPS exposures. Our data suggest that knocking down LRRK2 may protect from overt cell loss by inhibiting the recruitment of chronically activated proinflammatory myeloid cells. These results may provide value in the translation of LRRK2-targeting therapeutics to conditions where neuroinflammation may underlie aspects of neuronal dysfunction and degeneration.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

June 24, 2014

Volume

111

Issue

25

Start / End Page

9289 / 9294

Location

United States

Related Subject Headings

  • alpha-Synuclein
  • Substantia Nigra
  • Rats, Transgenic
  • Rats
  • Protein Serine-Threonine Kinases
  • Nitric Oxide Synthase Type II
  • Neurodegenerative Diseases
  • Myeloid Cells
  • Lipopolysaccharides
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
 

Citation

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MLA
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Daher, J. P. L., Volpicelli-Daley, L. A., Blackburn, J. P., Moehle, M. S., & West, A. B. (2014). Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats. Proc Natl Acad Sci U S A, 111(25), 9289–9294. https://doi.org/10.1073/pnas.1403215111
Daher, João P. L., Laura A. Volpicelli-Daley, Jonathan P. Blackburn, Mark S. Moehle, and Andrew B. West. “Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats.Proc Natl Acad Sci U S A 111, no. 25 (June 24, 2014): 9289–94. https://doi.org/10.1073/pnas.1403215111.
Daher JPL, Volpicelli-Daley LA, Blackburn JP, Moehle MS, West AB. Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats. Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):9289–94.
Daher, João P. L., et al. “Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats.Proc Natl Acad Sci U S A, vol. 111, no. 25, June 2014, pp. 9289–94. Pubmed, doi:10.1073/pnas.1403215111.
Daher JPL, Volpicelli-Daley LA, Blackburn JP, Moehle MS, West AB. Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats. Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):9289–9294.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

June 24, 2014

Volume

111

Issue

25

Start / End Page

9289 / 9294

Location

United States

Related Subject Headings

  • alpha-Synuclein
  • Substantia Nigra
  • Rats, Transgenic
  • Rats
  • Protein Serine-Threonine Kinases
  • Nitric Oxide Synthase Type II
  • Neurodegenerative Diseases
  • Myeloid Cells
  • Lipopolysaccharides
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2