Human Neural Stem Cell Systems to Explore Pathogen-Related Neurodevelopmental and Neurodegenerative Disorders

Abstract

Building and functioning of the human brain requires the precise orchestration and execution of myriad molecular and cellular processes, across a multitude of cell types and over an extended period of time. Dysregulation of these processes affects structure and function of the brain and can lead to neurodevelopmental, neurological, or psychiatric disorders. Multiple environmental stimuli affect neural stem cells (NSCs) at several levels, thus impairing the normal human neurodevelopmental program. In this review article, we will delineate the main mechanisms of infection adopted by several neurotropic pathogens, and the selective NSC vulnerability. In particular, TORCH agents, i.e., Toxoplasma gondii, others (including Zika virus and Coxsackie virus), Rubella virus, Cytomegalovirus, and Herpes simplex virus, will be considered for their devastating effects on NSC self-renewal with the consequent neural progenitor depletion, the cellular substrate of microcephaly. Moreover, new evidence suggests that some of these agents may also affect the NSC progeny, producing long-term effects in the neuronal lineage. This is evident in the paradigmatic example of the neurodegeneration occurring in Alzheimer's disease.

Keywords: Alzheimer’s disease; TORCH syndrome; human neural stem cells; microcephaly; neurodegeneration; neurodevelopment.

Figure 1

Schematic illustration of neocortical development. Neuroepithelial cells (NECs) undergo symmetric cell division to expand the initial pool and later transition into ventricular radial glia cells (vRGCs). vRGCs begin asymmetric cell division to generate another vRGC and a nascent projection neuron. Neurons then migrates radially from the ventricular zone (VZ) along the RGC basal processes into the cortical plate (CP). Early-born projection neurons (PNs) settle in the deep layers (Layers 5 and 6), and later-born neurons in upper layers. Additionally, some populations of RGC daughter cells convert themselves into intermediate progenitor cells (IPCs) or outer radial glial cells (oRGCs) in the subventricular zone (SVZ). After the neurogenic stages, gliogenesis occurs, generating astrocytes and oligodendrocytes.

Figure 2

Illustration of the major consequences elicited by TORCH infection in human neural stem cells (hNSCs). hNSCs can be infected by several TORCH pathogens such as Zika virus (ZIKV), Cytomegalovirus (CMV), Coxsackie B virus (CoxB), Toxoplasma gondii (T. gondii), and Herpes simplex virus (HSV). All these agents can lead to several and critical consequences such as cell death, proliferation impairment, unbalance of neurogenesis and gliogenesis, and migration impairment. Processes in bold are shared among TORCH pathogens. ER: endoplasmic reticulum.

Figure 3

Mature neurons are a target of specific TORCH agents. (a) Multiple infections sustained by different pathogens, such as Zika virus (ZIKV), Toxoplasma gondii (T. gondii), cytomegalovirus (CMV), and Herpes simplex virus (HSV), evoke detrimental effects in mature neurons, including cell death or substantial alterations in function. (b) HSV-1 infection sustains membrane depolarization with the consequent increase in intracellular calcium via voltage-gated calcium channels (VGCC) or through depletion from intracellular stores, such as the endoplasmic reticulum (ER). HSV-1 infection is also linked to amyloid precursor protein (APP) phosphorylation of Thr668 which facilitates the amyloidogenic APP cleavage by BACE1 (as known as β secretase) and the release of Aβ₄₂. AICD, APP intracellular domain. (c) A paradigmatic example of structural alteration due to viral infection is linked to the phosphorylation of the microtubule-associated protein MAPT (as known as Tau). Tau phosphorylation upon HSV-1 infection produces its release from microtubules with consequential loss in stability.