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Human Peripheral Blood Neutrophil Isolation for Interrogating the Parkinson's Associated LRRK2 Kinase Pathway by Assessing Rab10 Phosphorylation
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The Parkinson's Disease-Associated Protein Kinase LRRK2 Modulates Notch Signaling through the Endosomal Pathway

Yuzuru Imai1, Yoshito Kobayashi2, Tsuyoshi Inoshita1

  • 1Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Plos Genetics
|September 11, 2015
PubMed

Insights

Researchers discovered new proteins linked to Leucine-rich repeat kinase 2 (LRRK2) that affect Parkinson's disease (PD) pathology. These proteins modulate Notch signaling, impacting neural stem cell differentiation and dopaminergic neuron survival in PD.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Leucine-rich repeat kinase 2 (LRRK2) is implicated in Parkinson's disease (PD) pathogenesis.
  • Understanding LRRK2's molecular interactions is crucial for elucidating PD mechanisms.

Purpose of the Study:

  • Identify novel proteins interacting with LRRK2.
  • Investigate the role of these interactions in cellular pathways relevant to PD.
  • Determine the impact on Notch signaling and neuronal function.

Main Methods:

  • Protein-protein interaction studies to identify LRRK2-associated proteins.
  • Analysis of LRRK2 binding domains (ROC domain).
  • Investigation of cellular vesicle transport and Notch signaling pathways.

Main Results:

  • Two novel LRRK2-associated proteins, HERC2 (HECT-type ubiquitin ligase) and NEURL4 (adaptor-like protein), were identified.
  • LRRK2 interacts with NEURL4 and HERC2, linking it to vesicle transport and Notch signaling.
  • The LRRK2 complex modulates endosomal trafficking, stabilizing Delta-like 1 (Dll1)/Delta (Dl) and negatively regulating Notch signaling.
  • This regulation impacts neural stem cell differentiation and dopaminergic neuron survival, with effects enhanced by the LRRK2 R1441G mutation.

Conclusions:

  • Alterations in Notch signaling within mature neurons are a potential component of LRRK2-associated Parkinson's disease.
  • The identified LRRK2-HERC2-NEURL4 complex provides a new mechanistic link between LRRK2 and PD etiology.
  • Targeting this pathway may offer therapeutic strategies for Parkinson's disease.

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