LRRK2 Promotes Tau Accumulation, Aggregation and Release.

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Leucine-rich repeat kinase 2 (LRRK2) mutations are a primary cause of familial Parkinson's disease (PD).
• LRRK2's G2019S mutation enhances kinase function, implicating it in PD pathogenesis.
• Hyperphosphorylated Tau protein, a hallmark of Alzheimer's, is also found in PD brains.

Purpose of the Study:

• To investigate the interaction between LRRK2 and Tau protein in Parkinson's disease.
• To elucidate the role of LRRK2 kinase activity in Tau pathology.
• To explore the cellular mechanisms underlying LRRK2's effect on Tau.

Main Methods:

• Demonstrated the physical interaction between LRRK2 and Tau.
• Assessed the impact of LRRK2 on Tau species and secretion.
• Investigated the role of LRRK2 kinase activity in Tau regulation.
• Examined the effect of LRRK2 on proteasomal degradation pathways.

Main Results:

• LRRK2 interacts with Tau independently of its kinase activity.
• LRRK2 promotes the accumulation of non-monomeric and high-molecular weight Tau species.
• LRRK2 increases Tau secretion, linked to impaired proteasomal degradation.
• LRRK2-mediated proteasome impairment contributes to Tau pathology progression.

Conclusions:

• LRRK2 regulates intracellular Tau levels through proteasome impairment.
• The interaction between LRRK2 and Tau, independent of kinase activity, impacts PD pathology.
• Targeting the interplay between LRRK2 and proteasome activity may offer therapeutic strategies for PD.