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Higher Urine bis(Monoacylglycerol)Phosphate Levels in LRRK2 G2019S Mutation Carriers: Implications for Therapeutic Development
Movement disorders, 2020-01, Vol.35 (1), p.134-141
Alcalay, Roy N.
Hsieh, Frank
Tengstrand, Elizabeth
Padmanabhan, Shalini
Baptista, Marco
Kehoe, Caitlin
Narayan, Sushma
Boehme, Amelia K.
Merchant, Kalpana
2020
Details
Autor(en) / Beteiligte
Alcalay, Roy N.
Hsieh, Frank
Tengstrand, Elizabeth
Padmanabhan, Shalini
Baptista, Marco
Kehoe, Caitlin
Narayan, Sushma
Boehme, Amelia K.
Merchant, Kalpana
Titel
Higher Urine bis(Monoacylglycerol)Phosphate Levels in LRRK2 G2019S Mutation Carriers: Implications for Therapeutic Development
Ist Teil von
Movement disorders, 2020-01, Vol.35 (1), p.134-141
Ort / Verlag
Hoboken, USA: John Wiley & Sons, Inc
Erscheinungsjahr
2020
Link zum Volltext
Quelle
Wiley Online Library Journals Frontfile Complete
Beschreibungen/Notizen
Background LRRK2 mutations are a common cause of dominantly inherited PD. Previous studies showed decreases in urine levels of didocohexaenoyl (22:6) bis(monoacylglycerol)phosphate in LRRK2‐knockout mice and in non‐human primates treated with LRRK2 kinase inhibitors. We hypothesized that urine levels of bis(monoacylglycerol)phosphate isoforms will be higher in individuals with a PD‐causing gain‐of‐kinase function mutation, LRRK2 G2019S. The objective of this study was to investigate alterations in urinary phospholipids as biomarkers of LRRK2 mutations and Parkinson's disease status/phenotypes. Methods Ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) was used to assess 54 bioactive phospholipids in urine from the LRRK2 Cohort Consortium (n = 80). To confirm and extend the findings, urine from an independent LRRK2 cohort from Columbia University Irving Medical Center (n = 116) was used. Both cohorts were composed of LRRK2 G2019S carriers and non‐carriers with and without PD. Results In each cohort, 4 bis(monoacylglycerol)phosphate isoforms (di‐18:1‐bis[monoacylglycerol]phosphate, didocohexaenoyl [22:6] bis[monoacylglycerol] phosphate, 2,2′‐di‐22:6‐bis[monoacylglycerol]phosphate, and 2,2′‐di‐18:1‐bis[monoacylglycerol]phosphate) were significantly higher (2.5‐ to 4.3‐fold) in G2019S carriers compared with non‐carriers. Interestingly, 2,2′‐di‐18:1‐bis(monoacylglycerol)phosphate levels were marginally higher in LRRK2 carriers with PD than in those without PD (P = 0.045). Moreover, increased 2,2′ and total di‐22:6‐bis(monoacylglycerol)phosphate were associated with worse cognitive status assessed by the Montreal Cognitive Assessment (P = 0.0033 and 0.0144, respectively). Conclusions The observed association of bis(monoacylglycerol)phosphate isoforms with LRRK2 G2019S mutation, PD status among G2019S carriers, and correlation with cognitive decline suggest the potential use of urinary bis(monoacylglycerol)phosphate isoforms as biomarkers for clinical trials of LRRK2‐targeted therapies. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Sprache
Englisch
Identifikatoren
ISSN: 0885-3185
eISSN: 1531-8257
DOI: 10.1002/mds.27818
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6981003
Format
–
Schlagworte
Aged
,
Biomarkers
,
Clinical trials
,
Cognitive ability
,
Female
,
Heterozygote
,
Humans
,
Isoforms
,
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics
,
Liquid chromatography
,
LRRK2 protein
,
Male
,
Mass spectroscopy
,
Middle Aged
,
Movement disorders
,
Mutation
,
Mutation - genetics
,
Neurodegenerative diseases
,
Parkinson Disease - genetics
,
Parkinson Disease - physiopathology
,
Parkinson's disease
,
Parkinsonian Disorders - genetics
,
Phenotype
,
Phenotypes
,
Phosphate
,
Phospholipids
,
Urine
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