Effects on the serotoninergic system in sub-acute transmissible spongiform encephalopathies: current data, hypotheses, suggestions for experimentation

Summary 

Sub-acute transmissible spongiform encephalopathies (TSEs), or prion diseases, are affections in which little is known of their etiology. The predominant theory stipulates that an abnormal protease-resistant prion protein (PrP^res) would be infectious by directly inducing its defective conformation to the normal native protein (PrP^C). The function of PrP^C remains unknown. The preferred localization of PrP^C at the level of the synapses supposes a function in neuronal transmission. Several neurotransmitter systems (acetylcholine, GABA, dopamine, etc.) are damaged in TSEs, mainly the serotonin (5-HT) system. At a hypothetical level, PrP^C would play a trophic and functional role by regulating the capture of amino acid precursors of neurotransmitters and the functions of neuroreceptors, in particular regarding tryptophan and 5-HT receptors. By comparison with the modes of action of Ras proteins and of the envelope glycoprotein of jaagsiekte sheep retrovirus, the adaptation of an oncogenic model is suggested for the mode of action of PrP^res. The sequence of events could be the following: capture of PrP^res and forming of an abnormal receptor, chronic disturbance of transduction pathways, more particularly of the phosphatidylinositol-3 kinase (PI-3K)/protein kinase B (Akt)/glycogen synthetase kinase 3 (GSK 3)/Wnt-β catenin pathway, deregulation of the PrP gene and infrequent and transitory forming of abnormal RNA messengers and, finally, the forming of abnormal proteins and the deterioration of the serotoninergic system. The involvement of endogenous nucleic acids is supposed. The infectious agent of TSEs could be an ancestral form of retrovirus, such as a retrotransposon using the prion protein as an envelope glycoprotein. Pharmacological tests, by comparison with a rare disease of unknown etiology in cattle, bovine spastic paresis, are suggested with the amino acid precursors of neuromediators (tryptophan, tyrosine, glutamic acid, etc.) and with lithium, neuroprotector and regulator of the serotonergic system.

Abbreviations: TSEs, sub-acute transmissible spongiform encephalopathies, PrP, prion protein, PrP^C, normal protease-sensitive PrP, PrP^res, abnormal protease-resistant PrP, 5-HT, serotonin, 5-HIAA, 5-hydroxyindoleacetic acid, TRP, tryptophan, BSP, bovine spastic paresis, BSE, bovine spongiform encephalopathy, MAO, monoamine oxydase, Akt, protein kinase B, PIPLC, phosphatidylinositol-specific phospholipase C, GSK 3, glycogen synthetase kinase 3, PI-3K, phosphatidylinositol 3-kinase