Perturbed MAPK signaling in ASD: Impact of metal neurotoxicity

Abstract

The mitogen-activated protein kinase (MAPK) pathways are intracellular signaling pathways necessary for regulating various physiological processes, including neurodevelopment. The developing brain is vulnerable to toxic substances, and metals, such as lead, mercury, nickel, manganese, and others, have been proven to induce disturbances in the MAPK signaling pathway. Since a well-regulated MAPK is necessary for normal neurodevelopment, perturbation of the MAPK pathway results in neurodevelopmental disorders, including autism spectrum disorder (ASD). ASD affects brain parts responsible for communication, cognition, social interaction, and other patterned behaviors. Several studies have addressed the role of metals in the etiopathogenesis of ASD. Here, we briefly review the MAPK signaling pathway and its role in neurodevelopment. Furthermore, we highlight the role of metal toxicity in the development of ASD and how perturbed MAPK signaling may result in ASD.

Keywords: Autism; MAPK; Metal exposure; Neurodevelopment disorder.

Figure 1

MAPK in normal and perturbed neurodevelopment. Optimum developmental conditions will favor a well-regulated MAPK signaling, therefore normal intracellular functions and development, and consequently normal neurodevelopment. Exposure of the developing brain to neurotoxic substances results in perturbed MAPK signaling, resulting in NDDs such as ASD. ASD is characterized by a defect in social communication and restricted, repetitive sensory-motor behavior.

Figure 2

MAPK signaling pathway. In the MAPK signaling pathway, external stimuli initiate MAP4K/GTPases’ activation, which in turn phosphorylates and activates MAP3K. Activated MAP3K phosphorylates and activates MAP2K, which in turn phosphorylates and activates MAPK. Activated MAPK phosphorylates various other proteins in the cell, which consequently results in cellular responses. Other members of the MAPK family signaling pathway include ERK, p38, and JNK.

Figure 3

Mechanisms of metal-induced perturbed MAPK in ASD. Overexposure to metals (Pb, Hg, Mn, Ni) during neurodevelopment triggers perturbations in MAPK signaling and may contribute to ASD onset. Pb causes increased phosphorylation of ERK1/2 and p38 of the MAPK family. Hg activates MAPK and PKA/CREB pathway, followed by upregulation of c-fos and brain-derived neurotrophic factor (BDNF). Mn induces oxidative stress, increased p38, ERK1/2, JNK1/2/3, and caspase activities, and Ni is also a contributor to imbalanced antioxidants in oxidative stress.