Differential overexpression of SERPINA3 in human prion diseases

Abstract

Prion diseases are fatal neurodegenerative disorders with sporadic, genetic or acquired etiologies. The molecular alterations leading to the onset and the spreading of these diseases are still unknown. In a previous work we identified a five-gene signature able to distinguish intracranially BSE-infected macaques from healthy ones, with SERPINA3 showing the most prominent dysregulation. We analyzed 128 suitable frontal cortex samples, from prion-affected patients (variant Creutzfeldt-Jakob disease (vCJD) n = 20, iatrogenic CJD (iCJD) n = 11, sporadic CJD (sCJD) n = 23, familial CJD (gCJD) n = 17, fatal familial insomnia (FFI) n = 9, Gerstmann–Sträussler–Scheinker syndrome (GSS)) n = 4), patients with Alzheimer disease (AD, n = 14) and age-matched controls (n = 30). Real Time-quantitative PCR was performed for SERPINA3 transcript, and ACTB, RPL19, GAPDH and B2M were used as reference genes. We report SERPINA3 to be strongly up-regulated in the brain of all human prion diseases, with only a mild up-regulation in AD. We show that this striking up-regulation, both at the mRNA and at the protein level, is present in all types of human prion diseases analyzed, although to a different extent for each specific disorder. Our data suggest that SERPINA3 may be involved in the pathogenesis and the progression of prion diseases, representing a valid tool for distinguishing different forms of these disorders in humans.

CSF SerpinA1 in Creutzfeldt–Jakob disease and frontotemporal lobar degeneration

“…On the one hand, SerpinA1 may play a protective role as a molecular chaperone that prevents amyloid fibril formation and its O‐linked sialylation could act as a suppressor of pathogenetic self‐hyperphosphorylation as sialylation and phosphorylation share similar motifs . Alternatively, SerpinA1 post‐translational modifications might be detrimental by (1) blocking specific serine proteases and lead to impaired clearance of prion‐like proteins or (2) promoting the formation of a misfolded and self‐aggregate‐prone structure of SerpinA1 . On another issue, SerpinA1 is emerging as an important modulator of neuroinflammation …”

“…6 On another issue, recent studies showed that SerpinA3, another member of the serpin family, is significantly upregulated in brains and CSF of patients with prion disease, both at the mRNA and at the protein level, although to a different extent for each pathological subtype. 23,27,28 However, all these studies focused on the levels of total Relative peak area analysis for sCJD and FTLD subtypes. (A) Normalized peak area analysis of peak 0 for the sCJD subgroups.…”

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

“…Subsequently, Padmanabhan et al reported that anti‐chymotrypsin induces tau phosphorylation in neurons. In various neurological diseases, the expression of SERPINA3N in the brain has been found to be significantly upregulated . Recent studies have also shown that SERPINA3N is clearly related to many inflammation‐related diseases, such as hypothalamic inflammation, retinal neuroinflammation, allergic airway inflammation, myocarditis, and atherosclerosis .…”

“…Serpina3n encodes anti‐chymotrypsin, which is a widely expressed member of the serpin superfamily and has recently been recognized as a key component of the inflammatory response in the brain . In many neurological diseases, anti‐chymotrypsin in the brain has been found to be markedly upregulated . Serpina3n was also reported as a highly expressed gene in persistently active astrocytes .…”

“…25 In many neurological diseases, antichymotrypsin in the brain has been found to be markedly upregulated. 26,27 Serpina3n was also reported as a highly expressed gene in persistently active astrocytes. 28 The expression of SERPINA3N was significantly elevated in conjunction with neuroinflammation following retinal ischemia-reperfusion injury and hypothalamic neuroinflammation induced by a high-fat diet.…”