Molecular Mechanism of Neurodegeneration Induced by 4-Nonylphenol
Neurodegeneration, a progressive loss of nerve cells, occurs in many neurological disorders, including Alzheimer’s disease (AD) and Parkinson’s diseases (PD), as well as in dementia. The pathogenesis of these diseases is unknown, and recent evidence suggests that environmental factors, which act as endocrine-disrupting compounds (EDCs) could play a significant role in developing the disease process. 4-Nonylphenol (4-NP), an EDC, and a ubiquitous environmental toxin has been shown to affect brain development and may cause neurodegeneration. 4-NP is produced in large quantities in the U.S. and used as raw materials for making detergents, pesticides, plastics, paints, cosmetics, rubber, and other industrial/household products that lead to its widespread release to the environment. However, the underlying molecular mechanism of 4-NP-induced neurodegeneration is not understood. Recent results from our laboratory indicate that 4-NP inhibits nerve growth factor (NGF)-induced neuronal differentiation of PC12 cells, causes cellular aggregation and interferes with microtubule (an important component of the neuronal cytoskeleton) organization. The expression of tau, a microtubule-associated protein (MAP) known to play a key role in neurodegeneration was increased significantly in the presence of 4-NP. High-Resolution proteomic analysis of a cytoskeletal fraction (CSKF) reveals that 4-NP altered the proteomic landscape of CSK and increased the association of several proteins, including proteins of Alzheimer’s (AD) and Parkinson’s disease (PD) pathways, with the cytoskeleton (CSK). 4-NP has been shown to inhibit tubulin-Gbg interactions. Gbg is an important component of the GPCR (G protein-coupled receptor) signaling pathway and its interaction with tubulin/MTs has been shown to be important for MT assembly and neurite outgrowth. Based on these results I hypothesize that 4-NP induces neurodegeneration by disrupting cytoskeleton and altering expression/localization of Tau protein. We further hypothesize that Gbg and downstream PI3K/pAkt/pGSK3b signaling pathway is involved in this process. Because PC12 cells are not of neuronal origin, in the current study I also used human neuronal cells SHSY5Y. In Specific Aim 1, using biochemical, and immunoconfocal methodologies, I have demonstrated that 4-NP inhibited neurite formation and disrupted MT assembly and organization in both SHSY5Y and PC12 cells. Tau and tubulin localization was dramatically altered in the presence of 4-NP and no colocalization was observed as seen in control cells. In Specific Aim-2, I have conducted co-immunoprecipitation analysis and demonstrated the 4-NP significantly inhibited tubulin-Gbg interactions in SHSY5Y cells. In addition, the PI3K pathway was also affected by 4-NP as shown by inhibition of phosphorylation of Akt and GSK3b in the presence of 4-NP. Our study clearly demonstrates the potential risk of 4-NP in disrupting cytoskeleton and inducing neurodegeneration and should provide essential information in accessing the environment risk of 4-NP
Aranda Barroso, Michelle Alejandra, "Molecular Mechanism of Neurodegeneration Induced by 4-Nonylphenol" (2019). ETD Collection for University of Texas, El Paso. AAI27671277.