Altered Sphingolipid Hydrolase Activities and Alpha-Synuclein Level in Late-Onset Schizophrenia-Reference-Cited by-同舟云学术

Altered Sphingolipid Hydrolase Activities and Alpha-Synuclein Level in Late-Onset Schizophrenia

Published:2023-12-31 Issue:1 Volume:14 Page:30
ISSN:2218-1989
Container-title:Metabolites
language:en
Short-container-title:Metabolites

Author:

Usenko Tatiana¹²^ORCID,Bezrukova Anastasia¹²,Basharova Katerina²,Baydakova Galina²³,Shagimardanova Elena⁴^ORCID,Blatt Nataliya⁴,Rizvanov Albert⁴⁵^ORCID,Limankin Oleg⁶⁷,Novitskiy Maxim⁸^ORCID,Shnayder Natalia⁸,Izyumchenko Artem¹²,Nikolaev Mikhail¹²^ORCID,Zabotina Anna¹²,Lavrinova Anna²,Kulabukhova Darya¹²,Nasyrova Regina⁸^ORCID,Palchikova Ekaterina⁹,Zalutskaya Natalia⁹,Miliukhina Irina¹²¹⁰,Barbitoff Yury¹¹¹²¹³,Glotov Oleg¹¹¹²¹⁴^ORCID,Glotov Andrey¹¹¹⁵^ORCID,Taraskina Anastasia¹²,Neznanov Nikolai⁸⁹,Zakharova Ekaterina³,Pchelina Sofya¹²

Affiliation:

1. Department of Molecular Genetic and Nanobiological Technologies Research Center, Pavlov First Saint-Petersburg State Medical University, 197022 Saint Petersburg, Russia

2. Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Centre Kurchatov Institute, 188300 Gatchina, Russia

3. Research Center for Medical Genetics, 115478 Moscow, Russia

4. Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia

5. Division of Medical and Biological Sciences, Tatarstan Academy of Sciences, 420111 Kazan, Russia

6. Psychiatric Hospital No. 1 Named after P. P. Kashchenko, 195009 Saint Petersburg, Russia

7. North-Western Medical University Named after P. I.I. Mechnikov of the Ministry of Health of the Russian Federation, 191015 Saint Petersburg, Russia

8. Center for Personalized Psychiatry and Neurology of the N.N. V.M. Bekhtereva, 192019 Saint Petersburg, Russia

9. V.M. Bekhterev National Medical Research Center Psychiatry and Neurology, 192019 Saint Petersburg, Russia

10. Institute of the Human Brain of RAS, 197022 Saint Petersburg, Russia

11. D.O. Ott Research Institute for Obstetrics, Gynecology, and Reproductology, 199034 Saint Petersburg, Russia

12. Cerbalab Ltd., 197136 Saint Petersburg, Russia

13. Bioinformatics Institute, 197342 Saint Petersburg, Russia

14. Pediatric Research and Clinical Center of Infectious Diseases, 197022 Saint Petersburg, Russia

15. School of Medicine, St. Petersburg State University, 199034 Saint Petersburg, Russia

Abstract

Recent data described that patients with lysosomal storage disorders (LSDs) may have clinical schizophrenia (SCZ) features. Disruption of lipid metabolism in SCZ pathogenesis was found. Clinical features of schizophrenia (SCZ) have been demonstrated in patients with several lysosomal storage disorders (LSDs). Taking into account the critical role of lysosomal function for neuronal cells’ lysosomal dysfunction could be proposed in SCZ pathogenesis. The current study analyzed lysosomal enzyme activities and the alpha-synuclein level in the blood of patients with late-onset SCZ. In total, 52 SCZ patients with late-onset SCZ, 180 sporadic Parkinson’s disease (sPD) patients, and 176 controls were recruited. The enzymatic activity of enzymes associated with mucopolysaccharidosis (alpha-L-Iduronidase (IDUA)), glycogenosis (acid alpha-glucosidase (GAA)) and sphingolipidosis (galactosylceramidase (GALC), glucocerebrosidase (GCase), alpha-galactosidase (GLA), acid sphingomyelinase (ASMase)) and concentration of lysosphingolipids (hexosylsphingosine (HexSph), globotriaosylsphingosine (LysoGb3), and lysosphingomyelin (LysoSM)) were measured using LC-MS/MS. The alpha-synuclein level was estimated in magnetically separated CD45+ blood cells using the enzyme-linked immunosorbent assay (ELISA). Additionally, NGS analysis of 11 LSDs genes was conducted in 21 early-onset SCZ patients and 23 controls using the gene panel PGRNseq-NDD. Decreased ASMase, increased GLA activities, and increased HexSpn, LysoGb3, and LysoSM concentrations along with an accumulation of the alpha-synuclein level were observed in late-onset SCZ patients in comparison to the controls (p < 0.05). Four rare deleterious variants among LSDs genes causing mucopolysaccharidosis type I (IDUA (rs532731688, rs74385837) and type III (HGSNAT (rs766835582)) and sphingolipidosis (metachromatic leukodystrophy (ARSA (rs201251634)) were identified in five patients from the group of early-onset SCZ patients but not in the controls. Our findings supported the role of sphingolipid metabolism in SCZ pathogenesis. Aberrant enzyme activities and compounds of sphingolipids associated with ceramide metabolism may lead to accumulation of alpha-synuclein and may be critical in SCZ pathogenesis.

Funder

The Ministry of Science and Higher Education of the Russian Federation

Publisher

MDPI AG

Subject

Molecular Biology,Biochemistry,Endocrinology, Diabetes and Metabolism

Link

https://www.mdpi.com/2218-1989/14/1/30/pdf

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