Landscape of Protein Post-Translational Modifications in Age-Related Neurodegenerative Disorders: Implications in Protein Aggregation, Altered Cellular Processes, and Therapeutics

Accumulation of aggregated or nonfunctional proteins during the aging process is a common hallmark of degenerating neurons in various neurodegenerative disorders. Post-translational modifications (PTMs) such as acetylation, methylation, phosphorylation, and ubiquitination, etc. in combination with the protein quality control machinery such as autophagy and proteasome systems are essential for the degradation of these toxic aggregates, to maintain normal protein turnover and function of neurons. Abnormal protein quality control machinery primarily mediated by altered post-translational modifications of various proteins are linked to neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and many others. Accumulating evidence from the past two decades shows that targeting these PTMs with various small molecule activators or inhibitors restores synaptic and cognitive processes associated with these neurodegenerative diseases. Here, in this review, we highlight how these PTMs affect the accumulation and aggregation of nonfunctional proteins in various neurodegenerative diseases. Also, we highlight the current advances in exploring small molecule modulators of modifying enzymes as therapeutic options for these diseases.