Objective: The aim was to assess the possibility of differentiating synucleinopathies (Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA) by lysosomal hydrolases activity and sphingolipids concentration in peripheral blood primary monocytes-derived macrophages (PMDMs).

Background: Differential diagnosis of synucleinopathies is challenging due to clinical overlap at early stages of diseases. Molecular mechanisms of synucleinopathies are unknown. We previously showed pronounced alterations of lysosomal activities in blood of MSA and DLB patients [1].

Method: Lysosomal hydrolases activity (GCase, galactosylceramidase (GALC), alphagalactosidase A (GLA), acid sphingomyelinase (ASMase)) and sphingolipids concentration (hexosylsphingosine (HexSph), globotriaosylsphingosine (LysoGb3), lysosphingomyelin (LysoSM)) were assessed in PMDMs of PD (N=10), DLB (N=6), MSA (N=10) patients and controls (N=8) in triplicate by liquid chromatography-tandem mass spectrometry.

Results: Patients with PD, MSA, DLB were characterized by increased HexSph concentration in PMDMs (p<0.001). MSA patients were characterized by decreased GCase, GALC and ASMase activities compared to PD and controls (p<0.05), and decreased GLA activity compared to controls (p=0.007). Receiver Operating Characteristic curve analysis was performed to determine the cut-off values of studied parameters. Cut-off HexSph concentration for differentiating PD, MSA, DLB from healthy controls was determined (PD: 0.5 ng/ml, AUC=0.89, p=0.0009; DLB: 0.54 ng/ml, AUC=1, p=0.0006; MSA: 0.49 ng/ml, AUC=0.89, p=0.0002). Cut-off values of the hydrolases activity for differentiating MSA and healthy controls (GCase: 8 mM/l/h, AUC=0.84, p=0.0006; GALC: 2.04 mM/l/h, AUC=0.75, p=0.02; ASMase: 1.78 mM/l/h, AUC=0.88, p=0.0001; GLA: 12.3 mM/l/h, AUC=0.75, p=0.02), MSA and PD (GCase: 3.93 mM/l/h, AUC=0.76, p=0.019; GALC: 0.82 mM/l/h, AUC=0.79, p=0.01; ASMase: 2.47 mM/l/h, AUC=0.73, p=0.042) were also obtained.

Conclusion: Comprehensive assessment of GCase, GALC, ASMase, GLA activities in PMDMs may be considered as a potential biomarker for the differential diagnosis between MSA and other synucleinopathies.

References: 1. Usenko, T. S., Senkevich, K. A., Bezrukova, A. I., Baydakova, G. V., Basharova, K. S., Zhuravlev, A. S., Gracheva, E. V., Kudrevatykh, A. V., Miliukhina, I. V., Krasakov, I. V., Khublarova, L. A., Fursova, I. V., Zakharov, D. V., Timofeeva A.A., Irishina Y.A., Palchikova E.I., Zalutskaya N.M., Emelyanov A.K., Zakharova E.Y., Pchelina S.N. Impaired Sphingolipid Hydrolase Activities in Dementia with Lewy Bodies and Multiple System Atrophy. Molecular neurobiology, 2022. 59, p. 2277–2287

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MDS Abstracts - https://www.mdsabstracts.org/abstract/altered-activity-of-lysosomal-hydrolases-in-monocyte-derived-macrophages-as-potential-biomarker-for-differential-diagnosis-of-multiple-system-atrophy/