Usenko Tatiana, Bezrukova Anastasia, Basharova Katerina, Baydakova Galina, Shagimardanova Elena, Blatt Nataliya, Rizvanov Albert, Limankin Oleg, Novitskiy Maxim, Shnayder Natalia, Izyumchenko Artem, Nikolaev Mikhail, Zabotina Anna, Lavrinova Anna, Kulabukhova Darya, Nasyrova Regina, Palchikova Ekaterina, Zalutskaya Natalia, Miliukhina Irina, Barbitoff Yury, Glotov Oleg, Glotov Andrey, Taraskina Anastasia, Neznanov Nikolai, Zakharova Ekaterina, Pchelina Sofya
Department of Molecular Genetic and Nanobiological Technologies Research Center, Pavlov First Saint-Petersburg State Medical University, 197022 Saint Petersburg, Russia.
Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Centre Kurchatov Institute, 188300 Gatchina, Russia.
Metabolites. 2023 Dec 31;14(1):30. doi: 10.3390/metabo14010030.
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 ()), glycogenosis (acid alpha-glucosidase (GAA)) and sphingolipidosis (galactosylceramidase (), 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 ( < 0.05). Four rare deleterious variants among LSDs genes causing mucopolysaccharidosis type I ( (rs532731688, rs74385837) and type III ( (rs766835582)) and sphingolipidosis (metachromatic leukodystrophy ( (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.
近期数据表明，溶酶体贮积症（LSDs）患者可能具有临床精神分裂症（SCZ）特征。研究发现SCZ发病机制中存在脂质代谢紊乱。多种溶酶体贮积症（LSDs）患者已表现出精神分裂症（SCZ）的临床特征。鉴于溶酶体功能对神经元细胞的关键作用，推测溶酶体功能障碍可能参与SCZ的发病机制。本研究分析了晚发性SCZ患者血液中的溶酶体酶活性和α-突触核蛋白水平。共招募了52例晚发性SCZ患者、180例散发性帕金森病（sPD）患者和176例对照。使用液相色谱-串联质谱法（LC-MS/MS）检测与黏多糖贮积症（α-L-艾杜糖醛酸酶）、糖原贮积症（酸性α-葡萄糖苷酶（GAA））和鞘脂贮积症（半乳糖基神经酰胺酶、葡萄糖脑苷脂酶（GCase）、α-半乳糖苷酶（GLA）、酸性鞘磷脂酶（ASMase））相关的酶的活性以及溶血鞘脂（己糖神经鞘氨醇（HexSph）、球三糖神经鞘氨醇（LysoGb3）和溶血鞘磷脂（LysoSM））的浓度。使用酶联免疫吸附测定法（ELISA）在磁性分离的CD45 +血细胞中估计α-突触核蛋白水平。此外，使用基因检测板PGRNseq-NDD对21例早发性SCZ患者和23例对照进行了11个LSDs基因的二代测序（NGS）分析。与对照组相比，晚发性SCZ患者中观察到ASMase活性降低、GLA活性增加、HexSpn、LysoGb3和LysoSM浓度增加以及α-突触核蛋白水平积累（P < 0.05）。在早发性SCZ患者组的5例患者中鉴定出4种导致I型黏多糖贮积症（（rs532731688，rs74385837）和III型（（rs766835582））和鞘脂贮积症（异染性脑白质营养不良（（rs201251634））的LSDs基因中的罕见有害变异，但对照组中未发现。我们的研究结果支持鞘脂代谢在SCZ发病机制中的作用。与神经酰胺代谢相关的鞘脂异常酶活性和化合物可能导致α-突触核蛋白积累，并且可能在SCZ发病机制中起关键作用。
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