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Impaired Sphingolipid Hydrolase Activities in Dementia with Lewy Bodies and Multiple System Atrophy

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Abstract

The synucleinopathies are a group of neurodegenerative diseases characterized by the oligomerization of alpha-synuclein protein in neurons or glial cells. Recent studies provide data that ceramide metabolism impairment may play a role in the pathogenesis of synucleinopathies due to its influence on alpha-synuclein accumulation. The aim of the current study was to assess changes in activities of enzymes involved in ceramide metabolism in patients with different synucleinopathies (Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)). The study enrolled 163 PD, 44 DLB, and 30 MSA patients as well as 159 controls. Glucocerebrosidase, alpha-galactosidase, acid sphingomyelinase enzyme activities, and concentrations of the corresponding substrates (hexosylsphingosine, globotriaosylsphingosine, lysosphingomyelin) were measured by liquid chromatography tandem-mass spectrometry in blood. Expression levels of GBA, GLA, and SMPD1 genes encoding glucoceresobridase, alpha-galactosidase, and acid sphingomyelinase enzymes, correspondently, were analyzed by real-time PCR with TaqMan assay in CD45 + blood cells. Increased hexosylsphingosine concentration was observed in DLB and MSA patients in comparison to PD and controls (p < 0.001) and it was associated with earlier age at onset (AAO) of DLB (p = 0.0008). SMPD1 expression was decreased in MSA compared to controls (p = 0.015). Acid sphingomyelinase activity was decreased in DLB, MSA patients compared to PD patients (p < 0.0001, p < 0.0001, respectively), and in MSA compared to controls (p < 0.0001). Lower acid sphingomyelinase activity was associated with earlier AAO of PD (p = 0.012). Our data support the role of lysosomal dysfunction in the pathogenesis of synucleinopathies, namely, the pronounced alterations of lysosomal activities involved in ceramide metabolism in patients with MSA and DLB.

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Availability of Data and Materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors are grateful to all patients whose participation in the study made this analysis possible.

Funding

The study was supported by Russian foundation for basic research grant № 20–015-00116.

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Authors and Affiliations

  1. Petersburg Nuclear Physics Institute Named By B.P. Konstantinov of National Research Centre «Kurchatov Institute», 1, mkr. Orlova roshcha, 188300, Gatchina, Russia

    T. S. Usenko, K. A. Senkevich, A. I. Bezrukova, K. S. Basharova, A. S. Zhuravlev, A. K. Emelyanov & S. N. Pchelina

  2. Pavlov First Saint-Petersburg State Medical University, L’va Tolstogo str. 6-8, 197022, St. Petersburg, Russia

    T. S. Usenko, K. A. Senkevich, I. V. Miliukhina, A. A. Timofeeva, A. K. Emelyanov & S. N. Pchelina

  3. Research Center for Medical Genetics, Moskvorechie str. 1, Moscow, 115478, Russia

    G. V. Baydakova & E. Y. Zakharova

  4. Institute of the Human Brain of RAS, 9, Pavlova str, St. Petersburg, 197376, Russia

    E. V. Gracheva, A. V. Kudrevatykh, I. V. Miliukhina & Y. A. Irishina

  5. The Nikiforov Russian Center of Emergency and Radiation Medicine, Optikov str. 54, 197082, St. Petersburg, Russia

    I. V. Krasakov

  6. V.M. Bekhterevs National Medical Research Center Psychiatry and Neurology, 3 Bekhterev str., 192019, St. Petersburg, Russia

    L. A. Khublarova, I. V. Fursova, D. V. Zakharov, E. I. Palchikova & N. M. Zalutskaya

  7. Institute of Experimental Medicine, 12, Acad. Pavlov Str, 197376, Saint-Petersburg, Russia

    S. N. Pchelina

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  1. T. S. Usenko
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  2. K. A. Senkevich
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Contributions

Project was initiated by TU and SP. KS, MI, KI, LK, IF, DZ, AT, YI, EP, NZ, EG, and AK are doctors who generated the studied groups of patients with MSA, DLB, and PD. TU, AB, KB, AZ, and AE were involved in processing of the collection of biological samples (dry blood spots, CD45 + blood cells). TU and AB were involved in experimental design of study. Execution of biochemical assays have been done by TU, AB, KB, GB, and EZ. Statistical analyses were set up and performed by TU, AB, and KB. Figures were composed by TU and AB. TU, SP, and AB contributed to the interpretation of the data. TU wrote the first draft of the manuscript. The review and critique have been done by SP and KS. The manuscript was edited and finalized by SP and TU.

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Correspondence to T. S. Usenko.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by ethics committee of Pavlov First Saint-Petersburg State Medical University.

Informed consent was obtained from all individual participants included in the study.

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Usenko, T.S., Senkevich, K.A., Bezrukova, A.I. et al. Impaired Sphingolipid Hydrolase Activities in Dementia with Lewy Bodies and Multiple System Atrophy. Mol Neurobiol 59, 2277–2287 (2022). https://doi.org/10.1007/s12035-021-02688-0

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