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Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease

Ian Martin1, Jungwoo Wren Kim2, Byoung Dae Lee3

  • 1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA.

Cell
|April 15, 2014
PubMed

Insights

Parkinson's disease (PD) involves LRRK2 mutations. Researchers found ribosomal protein s15 is a key LRRK2 substrate, linking kinase activity to neurodegeneration and protein synthesis, offering new therapeutic targets for PD.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Mutations in leucine-rich repeat kinase 2 (LRRK2) are a significant cause of Parkinson's disease (PD).
  • While elevated LRRK2 kinase activity correlates with neurodegeneration, the specific downstream phosphosubstrate linking these processes remains unidentified.
  • Understanding LRRK2's molecular targets is crucial for elucidating PD pathogenesis.

Purpose of the Study:

  • To identify the pathogenic LRRK2 phosphosubstrate responsible for neurodegeneration in Parkinson's disease.
  • To investigate the role of ribosomal protein s15 in LRRK2-mediated neurotoxicity.
  • To explore the impact of LRRK2 activity on mRNA translation and protein synthesis.

Main Methods:

  • Utilized Drosophila and human neuron models of Parkinson's disease.
  • Investigated the function of ribosomal protein s15 using phosphodeficient (T136A) mutations.
  • Assessed dopamine neuron degeneration, locomotor deficits, neurite loss, and cell death.
  • Analyzed LRRK2-mediated effects on cap-dependent and cap-independent mRNA translation and overall protein synthesis.

Main Results:

  • Identified ribosomal protein s15 as a key pathogenic LRRK2 substrate in both Drosophila and human PD models.
  • Demonstrated that a phosphodeficient s15 mutant (T136A) rescues dopamine neuron degeneration and locomotor deficits in LRRK2 transgenic Drosophila.
  • Showed that the T136A s15 mutation significantly reduces LRRK2-mediated neurite loss and cell death in human neurons.
  • Revealed that pathogenic LRRK2 stimulates both cap-dependent and cap-independent mRNA translation, increasing protein synthesis, an effect preventable by the T136A s15 mutation.

Conclusions:

  • Ribosomal protein s15 is a critical mediator of LRRK2-associated neurotoxicity in Parkinson's disease.
  • Aberrant protein synthesis, driven by LRRK2 activity and involving ribosomal protein s15, represents a novel pathogenic mechanism in PD.
  • Targeting the LRRK2-s15 interaction and subsequent protein synthesis dysregulation may offer new therapeutic strategies for Parkinson's disease.

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