May 28, 2015

LRRK2 Promotes Tau Accumulation, Aggregation and Release

Molecular Neurobiology
Patrícia Silva GuerreiroKatrin Eckermann

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 d...Continue Reading

  • References49
  • Citations15

Citations

Mentioned in this Paper

Study
Biochemical Pathway
Proteasome Pathway
HEK293 Cells
Leucine-Rich Repeat Serine/Threonine-Protein Kinase 2
Protein Digestion
Genes
Neurofibrillary Degeneration (Morphologic Abnormality)
Protoplasm
Aggregation

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