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Assaying the Kinase Activity of LRRK2 in vitro
06:09

Assaying the Kinase Activity of LRRK2 in vitro

Published on: January 18, 2012

R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice

Youren Tong1, Antonio Pisani, Giuseppina Martella

  • 1Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.

Proceedings of the National Academy of Sciences of the United States of America
|August 12, 2009
PubMed

Insights

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's disease. The R1441C mutation impairs dopamine neurotransmission and D2 receptor function, potentially preceding neurodegeneration.

Area of Science:

  • Neuroscience
  • Genetics
  • Biochemistry

Background:

  • Dominantly inherited leucine-rich repeat kinase 2 (LRRK2) mutations are a frequent genetic cause of Parkinson's disease (PD).
  • The R1441 residue is critical, with three missense mutations identified in PD pathogenesis.

Purpose of the Study:

  • To investigate the pathogenic mechanism of LRRK2 dysfunction caused by the R1441C mutation.
  • To characterize the functional consequences of the R1441C mutation in a mouse model.

Main Methods:

  • Generated a knockin (KI) mouse model expressing the R1441C mutation under endogenous regulatory elements.
  • Assessed dopaminergic neurodegeneration, striatal dopamine levels, amphetamine (AMPH)-induced locomotor activity, and catecholamine release in cultured chromaffin cells.
  • Evaluated dopamine D2 receptor function and nigral neuron firing sensitivity to agonists and neurotransmitters.

Main Results:

  • Homozygous R1441C KI mice showed no overt neurodegeneration or altered striatal dopamine levels up to 2 years of age.
  • KI mice exhibited reduced AMPH-induced locomotor activity and impaired stimulated catecholamine release.
  • D2 receptor function was impaired, evidenced by decreased responses to quinpirole and reduced nigral neuron sensitivity to suppression by quinpirole, dopamine, or AMPH.

Conclusions:

  • The R1441C LRRK2 mutation impairs stimulated dopamine neurotransmission and dopamine D2 receptor function.
  • These functional deficits may serve as early pathogenic events preceding overt dopaminergic neurodegeneration in Parkinson's disease.

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