LRRK2 Promotes Tau Accumulation, Aggregation and Release

Mol Neurobiol. 2016 Jul;53(5):3124-3135. doi: 10.1007/s12035-015-9209-z. Epub 2015 May 27.

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; Protein accumulation; Protein degradation; Tau.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy
  • HEK293 Cells
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism*
  • Models, Biological
  • Molecular Weight
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Aggregates*
  • Protein Binding
  • Proteolysis
  • tau Proteins / metabolism*

Substances

  • Protein Aggregates
  • tau Proteins
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Proteasome Endopeptidase Complex