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Metabolic Labeling of Leucine Rich Repeat Kinases 1 and 2 with Radioactive Phosphate
11:31

Metabolic Labeling of Leucine Rich Repeat Kinases 1 and 2 with Radioactive Phosphate

Published on: September 18, 2013

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Loss of leucine-rich repeat kinase 2 (LRRK2) in rats leads to progressive abnormal phenotypes in peripheral organs

Marco A S Baptista1, Kuldip D Dave, Mark A Frasier

  • 1Research Programs, The Michael J. Fox Foundation for Parkinson's Research, New York, New York, United States of America.

Plos One
|November 19, 2013
PubMed

Insights

The LRRK2 knockout rat model shows progressive kidney, lung, and liver abnormalities starting by 2 months of age. This model is valuable for assessing Parkinson's disease drug safety.

Area of Science:

  • Biomedical research
  • Neuroscience
  • Toxicology

Background:

  • Parkinson's disease (PD) is a neurodegenerative disorder.
  • Leucine-rich repeat kinase 2 (LRRK2) mutations are a common genetic cause of PD.
  • LRRK2 knockout (KO) rat models are used to study PD pathogenesis and potential therapeutics.

Purpose of the Study:

  • To investigate the longitudinal pathology in LRRK2 KO rats.
  • To assess organ-specific changes and biochemical alterations over time.
  • To evaluate the utility of LRRK2 KO rats for preclinical safety assessments of LRRK2 inhibitors.

Main Methods:

  • Histopathology and ultrastructure examination of kidneys, lungs, spleen, heart, and liver.
  • Hematology, serum chemistry, and urinalysis.
  • Time-course evaluation at 1, 2, 4, 8, 12, and 16 months of age.

Main Results:

  • LRRK2 KO rats exhibited abnormal kidney morphology and staining from 2 months onwards.
  • Significant alterations in serum (phosphorus, creatinine, cholesterol, SDH, sodium, chloride) and urine parameters were observed.
  • Progressive renal, lung, and liver abnormalities were noted with age, while heart and spleen showed minimal changes.

Conclusions:

  • The LRRK2 KO rat model displays age-dependent renal, lung, and liver pathology.
  • These findings support the use of LRRK2 KO rats for evaluating the safety of LRRK2 kinase inhibitors.
  • This model aids in understanding potential off-target effects of PD therapeutics.

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