Study Rationale:
Mutations in the LRRK2 gene are a common cause of dominantly inherited Parkinson’s disease (PD). Previous studies showed that urine levels of a lipid [di-22:6-bis(monoacylglycerol)phosphate or BMP] were significantly higher in LRRK2 mutation carriers compared with noncarriers. Disease models without LRRK2 exhibit dramatically decreased levels of BMP and the enzyme β-N-acetylglucosamidase (NAG) activity in urine.
Hypothesis:
We hypothesize that BMP and NAG levels will be higher in the cerebrospinal fluid of people with the PD-causing gain of function mutation, LRRK2 G2019S.
Study Design:
Cerebrospinal fluid will be provided by the MJFF LRRK2 Cohort Consortium: 31 control volunteers, 24 people with PD and a LRRK2 mutation, 36 people with a LRRK2 mutation without PD, and 20 idiopathic (cause unknown) PD. BMP concentrations will be quantified by liquid chromatography with tandem mass spectrometry using an authentic reference standard. NAG activity will be determined by a colorimetric substrate conversion assay. The levels of BMP and NAG will be compared in LRRK2 mutation carriers and noncarriers with and without PD.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
BMP and NAG are biologically relevant, surrogate markers of LRRK2 activity that can be quantitated in patient samples. They can be used to 1) select treatments for a patient based on LRRK2 activity, 2) evaluate response to LRRK2 inhibitor drugs, and 3) select participants for clinical trials.
Next Steps for Development:
Future clinical studies will assess BMP and its isoforms in the cerebrospinal fluid of individuals with different LRRK2 mutations.