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

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.

[1]  N. Zalutskaya,et al.  Elevated Level of Blood Lysosphingolipids in Patients with Schizophrenia , 2023, Russian Journal of Genetics.

[2]  H. Kaya,et al.  Decreased serum levels of α‐synuclein in patients with schizophrenia and their unaffected siblings , 2023, Early intervention in psychiatry.

[3]  Yong Xu,et al.  Acid sphingomyelinase/ceramide system in schizophrenia: implications for therapeutic intervention as a potential novel target , 2022, Translational Psychiatry.

[4]  A. Vallée,et al.  Neuroinflammation in Schizophrenia: The Key Role of the WNT/β-Catenin Pathway , 2022, International journal of molecular sciences.

[5]  A. Emelyanov,et al.  Impaired Sphingolipid Hydrolase Activities in Dementia with Lewy Bodies and Multiple System Atrophy , 2022, Molecular Neurobiology.

[6]  E. Shagimardanova,et al.  Genomic Screening of Chronic Migraine Patients Identified Genes Linked to Drug and Endogenous Substances Metabolism , 2022, BioNanoScience.

[7]  Friederike Zunke,et al.  Pathological α-syn aggregation is mediated by glycosphingolipid chain length and the physiological state of α-syn in vivo , 2021, Proceedings of the National Academy of Sciences.

[8]  Guihu Zhao,et al.  The Association Between Lysosomal Storage Disorder Genes and Parkinson’s Disease: A Large Cohort Study in Chinese Mainland Population , 2021, Frontiers in Aging Neuroscience.

[9]  P. Khaitovich,et al.  Ceramides: Shared Lipid Biomarkers of Cardiovascular Disease and Schizophrenia , 2021, Consortium Psychiatricum.

[10]  H. Won,et al.  Shared Genetic Background between Parkinson’s Disease and Schizophrenia: A Two-Sample Mendelian Randomization Study , 2021, Brain sciences.

[11]  Agnieszka Wencel,et al.  Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease , 2021, International journal of molecular sciences.

[12]  T. Behl,et al.  Cross-talks among GBA mutations, glucocerebrosidase, and α-synuclein in GBA-associated Parkinson’s disease and their targeted therapeutic approaches: a comprehensive review , 2021, Translational neurodegeneration.

[13]  J. Hietala,et al.  Increased Risk of Parkinson's Disease in Patients With Schizophrenia Spectrum Disorders , 2021, Movement disorders : official journal of the Movement Disorder Society.

[14]  C. Zhuo,et al.  Lipidomics of the brain, retina, and biofluids: from the biological landscape to potential clinical application in schizophrenia , 2020, Translational Psychiatry.

[15]  C. Blauwendraat,et al.  Longitudinal Measurements of Glucocerebrosidase activity in Parkinson’s patients , 2020, Annals of clinical and translational neurology.

[16]  A. Futerman,et al.  Lysosomal Storage Disorders Shed Light on Lysosomal Dysfunction in Parkinson’s Disease , 2020, International journal of molecular sciences.

[17]  R. Schmidt-Kastner,et al.  Analysis of GWAS-Derived Schizophrenia Genes for Links to Ischemia-Hypoxia Response of the Brain , 2020, Frontiers in Psychiatry.

[18]  D. Martins‐de‐Souza,et al.  Novel Treatment Strategies Targeting Myelin and Oligodendrocyte Dysfunction in Schizophrenia , 2020, Frontiers in Psychiatry.

[19]  A. Pshezhetsky,et al.  Brain Pathology in Mucopolysaccharidoses (MPS) Patients with Neurological Forms , 2020, Journal of clinical medicine.

[20]  L. Parnetti,et al.  Lysosomal Ceramide Metabolism Disorders: Implications in Parkinson’s Disease , 2020, Journal of clinical medicine.

[21]  M. Daly,et al.  Exome sequencing in schizophrenia-affected parent-offspring trios reveals risk conferred by protein-coding de novo mutations , 2019, Nature Neuroscience.

[22]  J. Walters,et al.  Genome-wide association studies in schizophrenia: Recent advances, challenges and future perspective , 2019, Schizophrenia Research.

[23]  P. Wood.  Targeted lipidomics and metabolomics evaluations of cortical neuronal stress in schizophrenia , 2019, Schizophrenia Research.

[24]  V. Goyal,et al.  Evaluation of α-synuclein and apolipoprotein E as potential biomarkers in cerebrospinal fluid to monitor pharmacotherapeutic efficacy in dopamine dictated disease states of Parkinson’s disease and schizophrenia , 2019, Neuropsychiatric disease and treatment.

[25]  Jeong-A Lim,et al.  An emerging phenotype of central nervous system involvement in Pompe disease: from bench to bedside and beyond. , 2019, Annals of translational medicine.

[26]  W. Lukiw,et al.  The Role of Ceramide and Sphingosine-1-Phosphate in Alzheimer’s Disease and Other Neurodegenerative Disorders , 2019, Molecular Neurobiology.

[27]  L. Prakhova,et al.  SNCA variants and alpha-synuclein level in CD45+ blood cells in Parkinson’s disease , 2018, Journal of the Neurological Sciences.

[28]  A. Brice,et al.  Mutation analysis of Parkinson's disease genes in a Russian data set , 2018, Neurobiology of Aging.

[29]  S. Illarioshkin,et al.  Blood lysosphingolipids accumulation in patients with parkinson's disease with glucocerebrosidase 1 mutations , 2018, Movement disorders : official journal of the Movement Disorder Society.

[30]  A. Singleton,et al.  Lysosomal storage disorder gene variants in multiple system atrophy. , 2018, Brain : a journal of neurology.

[31]  M. Walterfang,et al.  Inborn errors of metabolism associated with psychosis: literature review and case–control study using exome data from 5090 adult individuals , 2018, Journal of Inherited Metabolic Disease.

[32]  P. Elliott,et al.  Anderson-Fabry disease in heart failure , 2018, Biophysical Reviews.

[33]  A. Schapira,et al.  Somatic copy number gains of &agr;-synuclein (SNCA) in Parkinson’s disease and multiple system atrophy brains , 2018, Brain : a journal of neurology.

[34]  P. Calabresi,et al.  Characterization of Brain Lysosomal Activities in GBA-Related and Sporadic Parkinson’s Disease and Dementia with Lewy Bodies , 2018, Molecular Neurobiology.

[35]  Masaaki Kato,et al.  Possible multiple system atrophy with predominant parkinsonism in a patient with chronic schizophrenia: a case report , 2018, BMC Psychiatry.

[36]  S. Ganesh,et al.  Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes , 2018, bioRxiv.

[37]  W. Chung,et al.  Alpha galactosidase A activity in Parkinson's disease , 2018, Neurobiology of Disease.

[38]  H. Ischiropoulos,et al.  The Convergence of Dopamine and α-Synuclein: Implications for Parkinson’s Disease , 2018, Journal of experimental neuroscience.

[39]  Jakob Grove,et al.  Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection , 2018, Nature Genetics.

[40]  Georgia M. Cook,et al.  The mechanism of glycosphingolipid degradation revealed by a GALC-SapA complex structure , 2018, Nature Communications.

[41]  S. Jeon,et al.  Reversible Conformational Conversion of α-Synuclein into Toxic Assemblies by Glucosylceramide , 2018, Neuron.

[42]  Simon C. Potter,et al.  Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease , 2017, Brain : a journal of neurology.

[43]  Mauricio O. Carneiro,et al.  Scaling accurate genetic variant discovery to tens of thousands of samples , 2017, bioRxiv.

[44]  J. Dodge.  Lipid Involvement in Neurodegenerative Diseases of the Motor System: Insights from Lysosomal Storage Diseases , 2017, Front. Mol. Neurosci..

[45]  Habibeh Khoshbouei,et al.  Alpha-synuclein modulates dopamine neurotransmission , 2017, Journal of Chemical Neuroanatomy.

[46]  F. Jamme,et al.  Long-term neurologic and cardiac correction by intrathecal gene therapy in Pompe disease , 2017, Acta Neuropathologica Communications.

[47]  I. Çetin,et al.  Decreased Expression of α-Synuclein, Nogo-A and UCH-L1 in Patients with Schizophrenia: A Preliminary Serum Study , 2017, Psychiatry investigation.

[48]  A. Kemper,et al.  Cognitive outcomes and age of detection of severe mucopolysaccharidosis type 1 , 2017, Genetics in Medicine.

[49]  S. Illarioshkin,et al.  Oligomeric α-synuclein and glucocerebrosidase activity levels in GBA-associated Parkinson’s disease , 2017, Neuroscience Letters.

[50]  J. Roiser,et al.  Membrane lipidomics in schizophrenia patients: a correlational study with clinical and cognitive manifestations , 2016, Translational psychiatry.

[51]  Daniel G. MacArthur,et al.  The ExAC browser: displaying reference data information from over 60 000 exomes , 2016, bioRxiv.

[52]  I. Duncan,et al.  Myelin repair by transplantation of myelin‐forming cells in globoid cell leukodystrophy , 2016, Journal of neuroscience research.

[53]  N. Hattori,et al.  Schizophrenia as a prodromal symptom in a patient harboring SNCA duplication. , 2016, Parkinsonism & related disorders.

[54]  A. Berardelli,et al.  Abnormal Salivary Total and Oligomeric Alpha-Synuclein in Parkinson’s Disease , 2016, PloS one.

[55]  Peilin Jia,et al.  Transcriptome Sequencing and Genome-wide Association Analyses Reveal Lysosomal Function and Actin Cytoskeleton Remodeling in Schizophrenia and Bipolar Disorder , 2014, Molecular Psychiatry.

[56]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[57]  K. Blennow,et al.  Levels of cerebrospinal fluid α-synuclein oligomers are increased in Parkinson’s disease with dementia and dementia with Lewy bodies compared to Alzheimer’s disease , 2014, Alzheimer's Research & Therapy.

[58]  W. Westbroek,et al.  Glucocerebrosidase is shaking up the synucleinopathies. , 2014, Brain : a journal of neurology.

[59]  A. Meyer-Lindenberg,et al.  Altered phospholipid metabolism in schizophrenia: A phosphorus 31 nuclear magnetic resonance spectroscopy study , 2013, Psychiatry Research: Neuroimaging.

[60]  M. Nalls,et al.  A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. , 2013, JAMA neurology.

[61]  A. Mirelman,et al.  The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease , 2013, Neurology.

[62]  Heng Li.  Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM , 2013, 1303.3997.

[63]  A. Malhotra,et al.  Genetics of schizophrenia: What do we know? , 2013, Current psychiatry.

[64]  Ellen Sidransky,et al.  The link between the GBA gene and parkinsonism , 2012, The Lancet Neurology.

[65]  I. McKeith,et al.  Glucocerebrosidase Mutations alter the endoplasmic reticulum and lysosomes in Lewy body disease , 2012, Journal of neurochemistry.

[66]  Han-Joon Kim,et al.  Increased Expression of Alpha-Synuclein by SNCA Duplication is Associated with Resistance to Toxic Stimuli , 2012, Journal of Molecular Neuroscience.

[67]  R. Pomès,et al.  Structure of saposin A lipoprotein discs , 2012, Proceedings of the National Academy of Sciences.

[68]  J. Gamble-George,et al.  α-Synuclein Stimulates a Dopamine Transporter-dependent Chloride Current and Modulates the Activity of the Transporter* , 2011, The Journal of Biological Chemistry.

[69]  K. Davis,et al.  Linking oligodendrocyte and myelin dysfunction to neurocircuitry abnormalities in schizophrenia , 2011, Progress in Neurobiology.

[70]  M. Mohammadi,et al.  Alpha- and beta-synucleins mRNA expression in lymphocytes of schizophrenia patients. , 2010, Genetic testing and molecular biomarkers.

[71]  M. Gluck,et al.  α-Synuclein gene duplication impairs reward learning , 2010, Proceedings of the National Academy of Sciences.

[72]  H. Hakonarson,et al.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data , 2010, Nucleic acids research.

[73]  P. McKenna,et al.  High throughput lipidomic profiling of schizophrenia and bipolar disorder brain tissue reveals alterations of free fatty acids, phosphatidylcholines, and ceramides. , 2008, Journal of proteome research.

[74]  R. Barbour,et al.  Red Blood Cells Are the Major Source of Alpha-Synuclein in Blood , 2008, Neurodegenerative Diseases.

[75]  J. Bertranpetit,et al.  Highly variable neural involvement in sphingomyelinase-deficient Niemann-Pick disease caused by an ancestral Gypsy mutation. , 2006, Brain : a journal of neurology.

[76]  P. Lee,et al.  The plasma alpha-synuclein levels in patients with Parkinson’s disease and multiple system atrophy , 2006, Journal of Neural Transmission.

[77]  W. Honer,et al.  Dementia as a complication of schizophrenia , 2001, Journal of neurology, neurosurgery, and psychiatry.

[78]  F. Jirik,et al.  Murine mucopolysaccharidosis type I: targeted disruption of the murine alpha-L-iduronidase gene. , 1997, Human molecular genetics.

[79]  L. Freysz,et al.  Acidic phospholipids inhibit the phospholipase D activity of rat brain neuronal nuclei , 1996, FEBS letters.

[80]  A. Schapira,et al.  Glucocerebrosidase Mutations in Parkinson Disease. , 2017, Journal of Parkinson's disease.

[81]  Ki-Young Jung,et al.  Comorbid schizophrenia and Parkinson’s disease: A case series and brief review , 2017 .

[82]  J. Stockman.  Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson's Disease , 2011 .

[83]  M. Farrer,et al.  Glucocerebrosidase mutations in diffuse Lewy body disease. , 2011, Parkinsonism & related disorders.

[84]  B. Dan,et al.  Metachromatic leukodystrophy without arylsulfatase A deficiency: a new case of saposin-B deficiency. , 2008, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[85]  J. Vidmar,et al.  Adult metachromatic leukodystrophy: disorganized schizophrenia-like symptoms and postpartum depression in 2 sisters. , 2005, Journal of psychiatry & neuroscience : JPN.

[86]  K. Higaki,et al.  [Niemann-Pick disease [type A and B] (acid sphingomyelinase deficiencies)]. , 1998, Ryoikibetsu shokogun shirizu.