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Higher Urine bis(Monoacylglycerol)Phosphate Levels in LRRK2 G2019S Mutation Carriers: Implications for Therapeutic

Roy N Alcalay1, Frank Hsieh2, Elizabeth Tengstrand2

  • 1Columbia University, Department of Neurology, New York, New York, USA.

Movement Disorders : Official Journal of the Movement Disorder Society
|September 11, 2019
PubMed
Abstract

Insights

Urinary bis(monoacylglycerol)phosphate levels are elevated in individuals with the LRRK2 G2019S mutation, a common cause of Parkinson's disease (PD). These findings suggest potential biomarkers for LRRK2-targeted therapies.

Area of Science:

  • Biochemistry
  • Genetics
  • Neuroscience

Background:

  • Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) are a frequent cause of inherited Parkinson's disease (PD).
  • Previous research indicated reduced urinary levels of specific phospholipids in LRRK2-deficient models and treated non-human primates.
  • This study investigated urinary bis(monoacylglycerol)phosphate (BMP) isoforms as potential biomarkers for LRRK2 mutations and PD.

Purpose of the Study:

  • To determine if urinary BMP isoform levels are higher in individuals carrying the PD-associated LRRK2 G2019S mutation.
  • To explore the utility of urinary phospholipids as biomarkers for LRRK2 mutations and Parkinson's disease phenotypes.

Main Methods:

  • Utilized ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to analyze 54 bioactive phospholipids in urine samples.
  • Examined two independent cohorts: the LRRK2 Cohort Consortium (n=80) and a cohort from Columbia University Irving Medical Center (n=116).
  • Included participants with and without PD, who were either LRRK2 G2019S carriers or non-carriers.

Main Results:

  • Four specific BMP isoforms were found to be significantly elevated (2.5- to 4.3-fold) in G2019S carriers compared to non-carriers in both cohorts.
  • A marginal increase in 2,2'-di-18:1-BMP was observed in LRRK2 carriers with PD versus those without PD (P=0.045).
  • Elevated levels of 2,2'-di-22:6-BMP and total di-22:6-BMP correlated with poorer cognitive status, as measured by the Montreal Cognitive Assessment.

Conclusions:

  • Urinary BMP isoforms show a strong association with the LRRK2 G2019S mutation.
  • These phospholipid alterations may serve as valuable biomarkers for assessing PD status in G2019S carriers and monitoring cognitive decline.
  • The findings support the potential use of urinary BMP isoforms as biomarkers in clinical trials targeting LRRK2 therapies.

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