Abstract
Heat shock cognate 70 (HSC70/HSPA8) is considered to be a promising candidate gene for schizophrenia (SCZ) due to its many essential functions and potential neuroprotective properties in the CNS (e.g., HSC70 is involved in the turnover of the synaptic proteins, synaptic vesicle recycling, and neurotransmitter homeostasis). An alteration in the expression of HSPA8 in SCZ has been reported. This implies that the genetic variants of HSPA8 might contribute to schizophrenia pathogenesis. The present study attempted to determine whether HSPA8 polymorphisms are associated with a susceptibility to schizophrenia or whether they have an impact on the clinical parameters of the disease in a Polish population. A total of 1066 participants (406 patients and 660 controls) were recruited for the study. Five SNPs of the HSPA8 gene (rs2236659, rs1136141, rs10892958, rs1461496, and rs4936770) were genotyped using TaqMan assays. There were no differences in the allele or genotype distribution in any of the SNPs in the entire sample. We also did not find any HSPA8 haplotype-specific associations with SCZ. A gender stratification analysis revealed that an increasing risk of schizophrenia was associated with the rs1461496 genotype in females (OR: 1.68, p < 0.05) in the recessive model. In addition, we found novel associations between HSPA8 SNPs (rs1136141, rs1461496, and rs10892958) and the severity of the psychiatric symptoms as measured by the PANSS. Further studies with larger samples from various ethnic groups are necessary to confirm our findings. Furthermore, studies that explore the functional contribution of the HSPA8 variants to schizophrenia pathogenesis are also needed.
Highlights
Schizophrenia (SCZ) is a complex neuropsychiatric disorder that is characterized by positive and negative symptoms and cognitive deficits (Owen et al 2016; Avramopoulos 2018)
This study attempted to determine whether polymorphisms in the HSPA8 gene are associated with the risk of SCZ or have an impact on the clinical parameters of the disease in a Polish population
While the direct effect of HSPA8/HSC70 on the development of schizophrenia needs to be established, there is some potential impact on the SCZ pathogenesis through the various critical functions that are performed by the HSC70 in the CNS (HSC70 is involved in the turnover of the synaptic proteins, clathrin-mediated endocytosis, neurotransmitter homeostasis, and participates in many neuroprotective mechanisms)
Summary
Schizophrenia (SCZ) is a complex neuropsychiatric disorder that is characterized by positive and negative symptoms and cognitive deficits (Owen et al 2016; Avramopoulos 2018). Heat shock cognate 70 (HSC70/HSPA8) is a constitutive molecular chaperone that belongs to the large HSP70 family. HSC70 is enriched in the developing CNS and unlike other HSP70 is preferentially expressed in neurons (Brown 2007). Proper protein folding, HSC70 participates in many of the neuroprotective mechanisms that are activated when cells are in inappropriate environments (ischemia, oxidative stress, inflammatory processes) as the brain develops (Liu et al 2012). The critical roles and potential neuroprotective properties of HSC70 in the CNS have been extensively studied in recent years (for a review, see Stetler et al 2010; Liu et al 2012). HSC70 was found to be involved in the turnover of the synaptic proteins and plays a prominent role in clathrin-mediated endocytosis, which is a key mechanism for synaptic vesicle recycling, which, in turn, is necessary for the maintenance of neurotransmission (Bechtold et al 2000; Gorenberg and Chandra 2017). It was found that HSC70 enables the efficient coupling between DA synthesis and storage by regulating the tyrosine hydroxylase (TH) activity (Parra et al 2016)
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