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Molecular Neurobiology

, Volume 53, Issue 5, pp 3124–3135 | Cite as

LRRK2 Promotes Tau Accumulation, Aggregation and Release

  • Patrícia Silva Guerreiro
  • Ellen Gerhardt
  • Tomás Lopes da Fonseca
  • Mathias Bähr
  • Tiago Fleming OuteiroEmail author
  • Katrin Eckermann
Article

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are known as the most frequent cause of familial Parkinson’s disease (PD), but are also present in sporadic cases. The G2019S-LRRK2 mutation is located in the kinase domain of the protein, and has consistently been reported to promote a gain of kinase function. Several proteins have been reported as LRRK2 substrates and/or interactors, suggesting possible pathways involved in neurodegeneration in PD. Hyperphosphorylated Tau protein accumulates in neurofibrillary tangles, a typical pathological hallmark in Alzheimer’s disease and frontotemporal dementia. In addition, it is also frequently found in the brains of PD patients. Although LRRK2 is a kinase, it appears that a putative interaction with Tau is phosphorylation-independent. However, the underlying mechanisms and the cellular consequences of this interaction are still unclear. In this study, we demonstrate an interaction between LRRK2 and Tau and that LRRK2 promotes the accumulation of non-monomeric and high-molecular weight (HMW) Tau species independent of its kinase activity. Interestingly, we found that LRRK2 increases Tau secretion, possibly as a consequence of an impairment of Tau proteasomal degradation. Our data highlight a mechanism through which LRRK2 regulates intracellular Tau levels, contributing to the progression of the pathology caused by the LRRK2-mediated proteasome impairment. In total, our findings suggest that the interplay between LRRK2 and proteasome activity might constitute a valid target for therapeutic intervention in PD.

Keywords

LRRK2 Tau Protein accumulation Protein degradation 

Notes

Acknowledgments

The authors would like to thank Dr. Mika Simons for the GFP-Rab6b plasmid. PSG and TLF are supported by fellowships from Fundação para Ciência e Tecnologia with the respective fellowships (SFRH/BD/61495/2009) and (SFRH/BD/74881/2010). KE, MB and TFO are supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)

Conflict of Interest

The authors declare no conflict of interest.

Author Contributions

PSG, EG, KE, and TFO designed the research; PSG, EG, TLF, and KE performed the experiments and analysed data; KE, MB, and TFO contributed with reagents, analytic tools, and scientific input; PSG, KE, and TFO wrote the paper.

Supplementary material

12035_2015_9209_MOESM1_ESM.docx (3.2 mb)
ESM 1 (DOCX 3295 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Patrícia Silva Guerreiro
    • 1
    • 2
  • Ellen Gerhardt
    • 2
  • Tomás Lopes da Fonseca
    • 1
    • 2
  • Mathias Bähr
    • 3
  • Tiago Fleming Outeiro
    • 1
    • 2
    • 4
    Email author
  • Katrin Eckermann
    • 3
  1. 1.Instituto de Medicina MolecularLisbonPortugal
  2. 2.Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the BrainUniversity Medical Center GöttingenGöttingenGermany
  3. 3.Department of Neurology, Center for Nanoscale Microscopy and Molecular Physiology of the BrainUniversity Medical Center GöttingenGöttingenGermany
  4. 4.Department of Neurodegeneration and Restorative ResearchUniversity Medical Center GoettingenGoettingenGermany

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