Di-docosahexaenoyl (22:6)-BMP
Di-docosahexaenoyl (22:6)-BMP
Bis(monoacylglycerol)phosphate (BMP) is a unique lysosomal phospholipid that plays important roles in lysosomal degradation pathways. The di-22:6-BMP, a specific species of BMP, is Nextcea’s patented biomarker of lysosomal storage dysfunction for Parkinson’s disease (LRRK2 mutation) diagnostics, drug efficacy assessments, and therapeutic uses. The di-22:6-BMP is measured in urine and plasma/serum to evaluate the impact of LRRK2 kinase inhibitors on lysosomal functions.
Bis(monoacylglycerol)phosphate (BMP)はリソゾームリン脂質の一種で、リソ ゾームの分解経路における重要な役割を担っています。BMPの特有の分子種 di-22:6-BMPは、Nextceaが特許権を持つリソゾーム貯蔵不全の特異的なバイ オマーカーで、パーキンソン病（LRRK2変異）の診断、薬効評価、治療への利用 が考えられます。リソゾーム機能に対するLRRK2キナーゼ阻害剤の効果を評価 するために、尿・血漿/血清中のDi-22:6-BMPを測定します。
In Figure 1, Urine di-22:6-BMP decreased following administration of LRRK2 inhibitors (MLi 2, PFE 360, and GNE-7915) in nonclinical animal studies presented by Michael J Fox Foundation [1][2].
Michael J Fox財団が提供した非臨床動物試験で、LRRK2阻害剤（MLi-2、PFE-360、GNE- 7915）の投与により尿中di-22:6-BMP量の低下が認められました[1][2]。
Figure 1
Figure 1
LRRK2, BMP, and Parkinson’s disease
LRRK2、BMP、パーキンソン病
Parkinson’s disease is linked to mutations in the leucine-rich repeat kinase 2 (LRRK2). These mutations impair endolysosomal/ lysosomal function and are neurotoxic [1][2]. BMP increases with lysosomal dysfunction associated with neurodegenerative diseases, including Parkinson’s disease [3][4]. Decreased BMP is observed in LRRK2 knockout rodents and animals treated with LRRK2 inhibitors, reflecting LRRK2 kinase activity. Di22:6-BMP provides an important tool for researchers to evaluate the effectiveness of new drug candidates to treat idiopathic and genetic forms of Parkinson’s disease (i.e., LRRK2, GBA, and PINK1).
パーキンソン病は、Leucine-rich repeat kinase 2（LRRK2）の変異と関連づけられています 。これらの変異によりエンドリソゾーム／リソゾーム機能が悪化し、神経毒性が生じます[1][2]。 パーキンソン病を含む神経変性疾患に関連したリソゾーム機能不全に伴って、BMPの増加が 認められます[3][4]。LRRK2ノックアウトマウスやLRRK2阻害剤で処理した動物では、LRRK2 キナーゼ活性に反映して、BMPの減少が認められます。Di-22:6-BMPは、新薬候補の薬効 評価を行う研究者たちにとって重要な手段となります。
In Figure 2, urine was collected from healthy donors, idiopathic PD patients, and LRRK2 G2019S mutation carriers with and without PD. Di-22:6-BMP and its 2,2’-di 22:6-BMP isomer were quantitated, with an authentic reference standard and internal standard, by high resolution UPLC-MS/MS. Biomarker concentrations in urine were normalized to urine creatinine. The di-22:6-BMP biomarker and its 2,2’-isomer were each >3-fold higher (p-value ≤0.0001) in LRRK2 G2019S mutation carriers, than non-carriers with and without PD [5].
In Figure 2, urine was collected from healthy donors, idiopathic PD patients, and LRRK2 G2019S mutation carriers with and without PD. Di-22:6-BMP and its 2,2’-di 22:6-BMP isomer were quantitated, with an authentic reference standard and internal standard, by high resolution UPLC-MS/MS. Biomarker concentrations in urine were normalized to urine creatinine. The di-22:6-BMP biomarker and its 2,2’-isomer were each >3-fold higher (p-value ≤0.0001) in LRRK2 G2019S mutation carriers, than non-carriers with and without PD [5].
The BMP biomarker levels in human urine
The BMP biomarker levels in human urine
Figure 2
Figure 2
Accurate LC-MS/MS Quantitation
高精度LC-MS/MS定量
Nextcea provides non-GLP and GLP LC-MS/MS assays for the quantitation of di-22:6-BMP in animal and human matrices. We employ a true reference standard for sensitive, specific and accurate di-22:6-BMP quantitation.
Nextceaは、動物及びヒトサンプル中のdi-22:6-BMP定量のためのLC-MS/MS分析（非GLP 及びGLP）を提供します。定量には真の標準物質を用いるので、高感度、特異的、正確なDi- 22:6-BMP定量が可能となります。
Nextcea’s patented biomarker di-22:6-BMP for lysosomal storage disorders, such as Parkinson’s disease (LRRK2 mutation) diagnostics, drug efficacy assessments, and therapeutic uses.
Nextceaの特許取得済みバイオマーカーdi-22:6-BMPは、パーキンソン病（LRRK2変異）など のリソゾーム貯蔵不全の診断、薬効評価、治療などに利用できます。
di-22:6-BMP
References
References
- Fuji RN, Flagella M, Baca M, Baptista MAS et al. (2015) Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Science Translational Medicine. 7(273): 273ra15. doi: 10.1126/scitranslmed.aaa3634
- Baptista MAS, Merchant K, Bryce D, Ellis M, et al. (2015) LRRK2 kinase inhibitors of different structural classes induce abnormal accumulation of lamellar bodies in type II pneumocytes in non-human primates but are reversible an without pulmonary functional consequences. https://www.michaeljfox.org/files/foundation/LSIposter_SfN2015.pdf
- Miranda AM, Lasiecka ZM, Xu Y, Neufeld J, Shahriar S, Simoes S, Chan RB, Oliveira TG, Small SA, Di Paolo G (2018). Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures. Nat Commun 9(1):291. doi: 10.1038/s41467-017-02533-w
- Miranda AM, Di Paolo GD. (2018) Endolysosomal dysfunction and exosome secretion: implications for neurodegenerative disorders. Cell Stress. 2(5):115-118. doi: 10.15698/cst2018.05.136
- Alcalay RN, Hsieh F, Tengstrand E, et al (2020) Higher Urine bis(Monoacylglycerol)Phosphate Levels in LRRK2 G2019S Mutation Carriers: Implications for Therapeutic Development. Movement Disorders, 35(1):134-141 Parkinson’s LRRK2 disease BMP biomarker