Effects of formaldehyde on protein (tau) aggregation and cytotoxicity

Abstract

The human body, including the brain, is producing and processing formaldehyde all the time. Formaldehyde is active in the reaction with biomacromolecules, especially with peptides and proteins. So neuronal proteins have chances to react directly with formaldehyde. Among the proteins, neuronal Tau is extremely prone to react with formaldehyde because Tau features in "wormlike" conformation, and its a-/e-amino groups are exposed to the protein exterior. Tau is a multifunctional protein which is able to bind to microtubule, actin, DNA and RNA, with its prolinerich domain and microtubule-binding domain. Tau promotes the melting temperature of DNA double strands and accelerates refolding of denatured DNA. Interaction between Tau and DNA forms a complex called "DNA-Tauosome", which may be the structure in resistance to the attack of free radicals, for example, reactive oxygen species (ROS). Treatment with formaldehyde inactivates Tau protein in the interaction with microtubule as well as DNA in which the formation of DNA-Tauosome is inhibited. Formaldehyde induces Tau aggregation which features in globular-like deposits stained with Congo red and probed by the fluorescence of thioflavin T (ThT). The cytotoxicity of globular-like aggregate leads to the impairment of cell viability and eventually to cell death. Lysosomes are classically considered as nonspecific systems in degradation of protein aggregation. Endogenous formaldehyde is mainly localized in lysosome. Abnormal lysosomes increase as aging and so does endogenous formaldehyde. Dysfunction of lysosome and formaldehyde metabolism could be the major risk factors to impede the cellular degradation and scavenging of protein aggregation. Since formaldehyde is actively and directly reacted with the side chains of peptides and proteins, we mainly discuss the effect of chemical modification with formaldehyde on morphology and function of neuronal Tau in this chapter, except for phosphorylation, glycosylation, and other modifications.