Abnormal protein post-translational modifications induces aggregation and abnormal deposition of protein, mediating neurodegenerative diseases

Abstract

Protein post-translational modifications (PPTMs) refer to a series of chemical modifications that occur after the synthesis of protein. Proteins undergo different modifications such as phosphorylation, acetylation, ubiquitination, and so on. These modifications can alter the protein’s structure, function, and interaction, thereby regulating its biological activity. In neurodegenerative diseases, several proteins undergo abnormal post-translational modifications, which leads to aggregation and abnormal deposition of protein, thus resulting in neuronal death and related diseases. For example, the main pathological features of Alzheimer’s disease are the aggregation of beta-amyloid protein and abnormal phosphorylation of tau protein. The abnormal ubiquitination and loss of α-synuclein are related to the onset of Parkinson’s disease. Other neurodegenerative diseases such as Huntington’s disease, amyotrophic lateral sclerosis, and so on are also connected with abnormal PPTMs. Therefore, studying the abnormal PPTMs in neurodegenerative diseases is critical for understanding the mechanism of these diseases and the development of significant therapeutic strategies. This work reviews the implications of PPTMs in neurodegenerative diseases and discusses the relevant therapeutic strategies.

Allosteric Activation of SIRT1 by 2,4-Dihydroxy-azaflavanone Averts MPP+-Mediated Dysfunction in Mitochondrial Biogenesis and Bioenergetics: Implications for Parkinson’s Disease

“…The progressive loss of dopamine neurons in the substantia nigra pars compacta (SNpc) region of the brain is a distinct feature of Parkinson’s disease (PD), which culminates into a wide range of motor and nonmotor symptoms, making PD a complex disorder. − Apart from a few symptomatic treatments, no disease-modifying therapies are available that either prevent or stop the progression of PD as of now. Studies from different familial mutant proteins associated with PD, such as α-synuclein, parkin, Pink1, LRRK2, UCHL1 etc., clearly infer that a great majority of the pathways affected in PD culminate in the mitochondrial quality control or protein degradation mechanisms. − Earlier studies from the literature indicate that mitochondria are the primary organelles that get affected in PD, leading to a cascade of downstream abnormalities. − In fact, several PD mimetics were found to be the inhibitors of mitochondrial respiration. ,− While the central role of mitochondria is to generate ATP for maintaining neuronal activity in the brain, it also regulates reactive oxygen species (ROS) and calcium homeostasis along with oxidative phosphorylation. − Further, mitochondrial ROS induces various apoptotic and posttranslational modifications on α-synuclein, such as oxidation, nitration etc., leading to aggregated forms of protein, which were surmised to play a precipitating role in the pathophysiology of PD. ,− …”