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A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration

Elie Maksoud1, Edward H Liao1, A Pejmun Haghighi1

  • 1Buck Institute for Research on Aging, Novato, CA 94945, USA.

Cell Reports
|February 14, 2019
PubMed

Insights

Pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) cause neuron loss. Targeting Furin 1 or bone morphogenic protein (BMP) signaling in glial cells protects against this neurodegeneration, suggesting new Parkinson

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) are linked to age-dependent dopaminergic (DA) neuron loss.
  • LRRK2's role in neurodegeneration, particularly in Parkinson's disease, is under investigation.

Purpose of the Study:

  • To identify LRRK2's translational targets in DA neurons.
  • To investigate the role of Furin 1 and bone morphogenic protein (BMP) signaling in LRRK2-induced neurodegeneration.
  • To explore a potential neuron-glial signaling cascade in Parkinson's disease pathogenesis.

Main Methods:

  • Utilized transgenic models to study LRRK2 effects.
  • Investigated the expression and function of Furin 1 and its substrate Gbb.
  • Analyzed the accumulation of phosphorylated Mad (pMad) in glial cells.
  • Examined the impact of targeting BMP pathway members specifically in glial cells.

Main Results:

  • Furin 1 was identified as a translational target of LRRK2 in DA neurons.
  • Knockdown of Furin 1 or Gbb protected against LRRK2-induced DA neuron loss.
  • LRRK2 and paraquat exposure increased Furin 1 levels and induced BMP signaling in glia.
  • Targeting the BMP pathway exclusively in glia conferred protection against neurotoxicity.

Conclusions:

  • A neuron-glial BMP-signaling cascade is implicated in age-dependent neurodegeneration.
  • This pathway is critical in models of Parkinson's disease.
  • Targeting this cascade offers potential therapeutic strategies for Parkinson's disease.
Keywords:
BMP signalingFurin1LRRK2Parkinson’s diseaseagingglianeurodegenerationtranslation

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