Abstract
Alongside biological, psychological, and social risk factors, psychotic syndromes may be related to disturbances of neuronal migration. This highly complex process characterizes the developing brain of the fetus, the early postnatal brain, and the adult brain, as reflected by changes within the subventricular zone and the dentate gyrus of the hippocampus, where neurogenesis persists throughout life. Psychosis also appears to be linked to human cytomegalovirus (HCMV) infection. However, little is known about the connection between psychosis, HCMV infection, and disruption of neuronal migration. The present study addresses the hypothesis that HCMV infection may lead to mental disorders through mechanisms of autoimmune cross-reactivity. Searching for common peptides that underlie immune cross-reactions, the analyses focus on HCMV and human proteins involved in neuronal migration. Results demonstrate a large overlap of viral peptides with human proteins associated with neuronal migration, such as ventral anterior homeobox 1 and cell adhesion molecule 1 implicated in GABAergic and glutamatergic neurotransmission. The present findings support the possibility of immune cross-reactivity between HCMV and human proteins that—when altered, mutated, or improperly functioning—may disrupt normal neuronal migration. In addition, these findings are consistent with a molecular and mechanistic framework for pathological sequences of events, beginning with HCMV infection, followed by immune activation, cross-reactivity, and neuronal protein variations that may ultimately contribute to the emergence of mental disorders, including psychosis.
Highlights
Generated neurons migrate from their site of origin to specific brain areas and subregions, a process that involves adaptation with different degrees of complexity [1, 2]
Following the procedure described under Methods, we found that 41 human cytomegalovirus (HCMV) heptapeptides are repeatedly distributed among 26 proteins associated with neuronal migration
The heptapeptides AVENGDS, DRGGGGG, INKRVKR, KPGASAA, LKPGASA, QTVTSTP, SSSSTSH, and YQRFLRE are HCMV molecular signatures of the human proteins associated with neuronal migration SAV1, sonic hedgehog protein (SHH), MAGI2, SMAD2, SMAD3, ULK1, and ACK1, respectively
Summary
Generated neurons migrate from their site of origin to specific brain areas and subregions, a process that involves adaptation with different degrees of complexity [1, 2]. Cell cycle, and angiogenesis are implicated in neuronal migration. Disruption of this process has been related to severe malformations of cortical development (lissencephaly, schizencephaly, neuronal eterotopia, polymicrogyria) [7] and to psychosis [8,9,10]. The relationship between macroand microscopic structural brain anomalies and psychosis appears to be unclear, and disruption of cellular function has been hypothesized [11, 12]. Altered migration and development of GABAergic cortical interneurons have been linked to schizophrenia and to depression and anxiety disorders and seem to be strongly dependent on other neurotransmitter networks, such as dopaminergic and glutamatergic systems [14,15,16]
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