Category: Parkinsonism, Atypical: MSA
Objective: To estimate whether alteration of lysosomal activities contributes to synucleinophaties pathogenesis.
Background: Multiple system atrophy (MSA) belongs to a group of neurodegenerative disorders termed synucleinopathies, which also include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) [1]. Molecular mechanisms of synucleinophaties are unknown. Last data suggest that lysosomal dysfunction may play a pivotal role in synucleinopathies pathogenesis [2].
Method: 28 MSA patients, 35 DLB patients, 132 PD patients and 135 controls were enrolled. GBA, SMPD1, GLA expression levels were analyzed by real-time PCR with TaqMan assay in CD45+ peripheral blood cells. Enzyme activities (glucoceresobridase (GCase), alpha-galactosidase (GLA), acid sphingomyelinase (ASM)) and substrate concentrations (hexosylsphingosine (HexSph), globotriaosylsphingosine (LysoGb3), lysosphingomyelin (LysoSM)) were measured by liquid chromatography tandem-mass spectrometry in dry blood spots.
Results: Elevated HexSph concentration was found in DLB and MSA patients compared to PD and controls (p<0.01) with no differences in GBA expression and GCase activity between groups (p>0.05). Higher HexSph concentration was associated with increased risk of MSA (OR=1.53, p=0.0002) and DLB (OR=1.53, p<0.0001). Decreased ASM activity was found in MSA and DLB compared to PD patients (p<0.001) and in MSA patients compared to DLB patients (p=0.044) with decrease of LysoSM concentration in MSA than in controls (p=0.0036) and DLB (p=0.0072). Higher ASM activity was associated with lower odds of MSA and DLB status (OR=0.48, p=0.0001; OR=0.67, p=0.003). Higher LysoSM concentrations was linked with lower odds of PD and MSA status (OR=0.65, p=0.001; OR=0.52, p=0.003). SMPD1 expression was decreased in PD compared to controls (p=0.0059). GLA activity was increased in MSA patients compared to controls (p=0.03). Increased GLA activity was associated with increased MSA risk (OR=1.26, p=0.041). GLA expression was decreased in DLB compared to all groups (p<0.05). There were no differences in LysoGb3 concentration between groups (p>0.05).
Conclusion: Our data showed that MSA as DLB are characterized by increased HexSph concentration compared to PD and controls and decreased ASM activity compared to PD with more pronounced variation of ASM activity in MSA and these alterations are associated with increase of MSA and DLB risk. The study was supported by RFBR №20-01500116.
References: 1. Fanciulli A., Wenning G.K.. Multiple-system atrophy // New England Journal of Medicine, 2015. – V. 372 – P. 249–263. 2. Sardi S.P., Cheng S.H., Shihabuddin L.S. Gaucher-related synucleinopathies: The examination of sporadic neurodegeneration from a rare (disease) angle // Prog Neurobiol, 2015. – V.125. – P.47-62
To cite this abstract in AMA style:
A. Bezrukova, K. Basharova, D. Bogdanova, K. Senkevich, A. Zhuravlev, E. Gracheva, I. Miliukhina, G. Baydakova, E. Zakharova, A. Emelyanov, S. Pchelina, T. Usenko. Alteration of lysosomal enzymatic activities in patients with multiple system atrophy [abstract]. Mov Disord. 2021; 36 (suppl 1). https://www.mdsabstracts.org/abstract/alteration-of-lysosomal-enzymatic-activities-in-patients-with-multiple-system-atrophy/. Accessed June 15, 2025.« Back to MDS Virtual Congress 2021
MDS Abstracts - https://www.mdsabstracts.org/abstract/alteration-of-lysosomal-enzymatic-activities-in-patients-with-multiple-system-atrophy/