LRRK2 and GBA1 variant carriers have higher urinary bis(monacylglycerol) phosphate concentrations in PPMI cohorts

Kalpana M Merchant; Tanya Simuni; Janel Fedler; Chelsea Caspell-Garcia; Michael Brumm; Kelly N H Nudelman; Elizabeth Tengstrandt; Frank Hsieh; Roy N Alcalay; Christopher Coffey; Lana Chahine; Tatiana Foroud; Andrew Singleton; Daniel Weintraub; Samantha Hutten; Todd Sherer; Brit Mollenhauer; Andrew Siderowf; Caroline Tanner; Ken Marek; the Parkinson’s Progression Markers Initiative

doi:10.1038/s41531-023-00468-2

LRRK2 and GBA1 variant carriers have higher urinary bis(monacylglycerol) phosphate concentrations in PPMI cohorts

NPJ Parkinsons Dis. 2023 Feb 28;9(1):30. doi: 10.1038/s41531-023-00468-2.

Authors

Kalpana M Merchant¹, Tanya Simuni², Janel Fedler³, Chelsea Caspell-Garcia³, Michael Brumm³, Kelly N H Nudelman⁴, Elizabeth Tengstrandt⁵, Frank Hsieh⁵, Roy N Alcalay⁶, Christopher Coffey³, Lana Chahine⁷, Tatiana Foroud⁸, Andrew Singleton⁹, Daniel Weintraub¹⁰, Samantha Hutten¹¹, Todd Sherer¹¹, Brit Mollenhauer¹², Andrew Siderowf¹⁰, Caroline Tanner¹³, Ken Marek¹⁴; the Parkinson’s Progression Markers Initiative

Affiliations

¹ Northwestern University Feinberg School of Medicine, Chicago, IL, USA. kalpana.merchant@northwestern.edu.
² Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
³ The University of Iowa, Iowa City, IA, USA.
⁴ Indiana University School of Medicine, Indianapolis, IN, USA.
⁵ Nextcea, Inc, Woburn, MA, USA.
⁶ Columbia University, New York, NY, USA.
⁷ University of Pittsburg, Pittsburgh, PA, USA.
⁸ Indiana University, Indianapolis, IN, USA.
⁹ National Institute on Aging, NIH, Bethesda, MD, USA.
¹⁰ The University of Pennsylvania, Philadelphia, PA, USA.
¹¹ The Michael J Fox Foundation for Parkinson's Research, New York, NY, USA.
¹² University Medical Center Goettingen, Parcacelsus Kliniken Germany, Göttingen, Germany.
¹³ University of California San Francisco, San Francisco, CA, USA.
¹⁴ Institute for Neurodegenerative Disorders, New Haven, CT, USA.

Abstract

We quantified concentrations of three isoforms of the endolysosomal lipid, bis(monoacylglycerol) phosphate (BMP) in the urine of deeply phenotyped cohorts in the Parkinson's Progression Markers Initiative: LRRK2 G2019S PD (N = 134) and non-manifesting carriers (NMC) (G2019S+ NMC; N = 182), LRRK2 R1441G PD (N = 15) and R1441G+ NMC (N = 15), GBA1 N409S PD (N = 76) and N409S+ NMC (N = 178), sporadic PD (sPD, N = 379) and healthy controls (HC) (N = 190). The effects of each mutation and disease status were analyzed using nonparametric methods. Longitudinal changes in BMP levels were analyzed using linear mixed models. At baseline, all LRRK2 carriers had 3-7× higher BMP levels compared to HC, irrespective of the disease status. GBA1 N409S carriers also showed significant, albeit smaller, elevation (~30-40%) in BMP levels compared to HC. In LRRK2 G2019S PD, urinary BMP levels remained stable over two years. Furthermore, baseline BMP levels did not predict disease progression as measured by striatal DaT imaging, MDS-UPDRS III Off, or MoCA in any of the cohorts. These data support the utility of BMP as a target modulation biomarker in therapeutic trials of genetic and sPD but not as a prognostic or disease progression biomarker.