Role of TMAO on Folding Behavior of Various Proteins Associated with Neurodegeneration

One common hallmark for all neurodegenerative diseases (including Alzheimer’s, Parkinson’s, Huntington’s, ataxia) is the presence of toxic protein inclusions (or protein oligomers) in various regions of the brain. For instance, Aβ accumulation is associated with Alzheimer’s disease. Oligomers of α-synuclein, Htt, and PrPsc are associated with Parkinson’s, Huntington’s, and Prion disease respectively. The presence of these oligomers is believed to be the basic cause of oxidative stress, neuro-inflammation, and synaptic dysfunctions leading to the apoptotic death of cells. Attempts have been made to develop appropriate inhibitors of such toxic inclusions. Various phytochemicals, synthetic compounds, and small peptides have already appeared as promising molecules for inhibiting these toxic inclusions. One important molecule that is produced by the human gut-microbiota, trimethylamine N-oxide (TMAO), has been extensively studied for its potential to suppress protein aggregation. Recently, TMAO has been appreciated as an excellent chemical chaperone based on its effect to modulate protein folding, aggregation, and its ability to regulate protein quality control in the ER. In the light of the neurodegenerative diseases, various studies have been conducted about the potential impact of TMAO against the formation of many toxic inclusions. In the present chapter, we attempt to elucidate the potentiality of TMAO as a drug to suppress the formation of toxic protein inclusions associated with various neurodegenerative diseases. Future insights have also been appropriately discussed.