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14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening.

Publication ,  Journal Article
Lavalley, NJ; Slone, SR; Ding, H; West, AB; Yacoubian, TA
Published in: Hum Mol Genet
January 1, 2016

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common known cause of inherited Parkinson's disease (PD), and LRRK2 is a risk factor for idiopathic PD. How LRRK2 function is regulated is not well understood. Recently, the highly conserved 14-3-3 proteins, which play a key role in many cellular functions including cell death, have been shown to interact with LRRK2. In this study, we investigated whether 14-3-3s can regulate mutant LRRK2-induced neurite shortening and kinase activity. In the presence of 14-3-3θ overexpression, neurite length of primary neurons from BAC transgenic G2019S-LRRK2 mice returned back to wild-type levels. Similarly, 14-3-3θ overexpression reversed neurite shortening in neuronal cultures from BAC transgenic R1441G-LRRK2 mice. Conversely, inhibition of 14-3-3s by the pan-14-3-3 inhibitor difopein or dominant-negative 14-3-3θ further reduced neurite length in G2019S-LRRK2 cultures. Since G2019S-LRRK2 toxicity is likely mediated through increased kinase activity, we examined 14-3-3θ's effects on LRRK2 kinase activity. 14-3-3θ overexpression reduced the kinase activity of G2019S-LRRK2, while difopein promoted the kinase activity of G2019S-LRRK2. The ability of 14-3-3θ to reduce LRRK2 kinase activity required direct binding of 14-3-3θ with LRRK2. The potentiation of neurite shortening by difopein in G2019S-LRRK2 neurons was reversed by LRRK2 kinase inhibitors. Taken together, we conclude that 14-3-3θ can regulate LRRK2 and reduce the toxicity of mutant LRRK2 through a reduction of kinase activity.

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Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

January 1, 2016

Volume

25

Issue

1

Start / End Page

109 / 122

Location

England

Related Subject Headings

  • Serine
  • Proteins
  • Protein Serine-Threonine Kinases
  • Protein Isoforms
  • Phosphorylation
  • Parkinson Disease
  • Neurons
  • Neurites
  • Mutation
  • Mice, Transgenic
 

Citation

APA
Chicago
ICMJE
MLA
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Lavalley, N. J., Slone, S. R., Ding, H., West, A. B., & Yacoubian, T. A. (2016). 14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening. Hum Mol Genet, 25(1), 109–122. https://doi.org/10.1093/hmg/ddv453
Lavalley, Nicholas J., Sunny R. Slone, Huiping Ding, Andrew B. West, and Talene A. Yacoubian. “14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening.Hum Mol Genet 25, no. 1 (January 1, 2016): 109–22. https://doi.org/10.1093/hmg/ddv453.
Lavalley NJ, Slone SR, Ding H, West AB, Yacoubian TA. 14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening. Hum Mol Genet. 2016 Jan 1;25(1):109–22.
Lavalley, Nicholas J., et al. “14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening.Hum Mol Genet, vol. 25, no. 1, Jan. 2016, pp. 109–22. Pubmed, doi:10.1093/hmg/ddv453.
Lavalley NJ, Slone SR, Ding H, West AB, Yacoubian TA. 14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening. Hum Mol Genet. 2016 Jan 1;25(1):109–122.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

January 1, 2016

Volume

25

Issue

1

Start / End Page

109 / 122

Location

England

Related Subject Headings

  • Serine
  • Proteins
  • Protein Serine-Threonine Kinases
  • Protein Isoforms
  • Phosphorylation
  • Parkinson Disease
  • Neurons
  • Neurites
  • Mutation
  • Mice, Transgenic