Novel molecular targets and mechanisms for neuroprotective modulation in neurodegenerative disorders.

Abstract

BACKGROUND Neuronal death underlies the symptoms of several human neurological disorders, including Alzheimer's, Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis that their precise pathophysiology have not yet been elucidated. According to various studies the prohibition is the best therapy with neuroprotective approaches which are advanced and safe methods. METHODS This review summarizes some of the already-known and newly emerged neuroprotective targets and strategies that their experimental effects have been reported. Accordingly, literature was studied from 2000 to 2021 and appropriate articles were searched in Google Scholar and Scopus with the keywords given in the Keywords section of the current review. RESULTS Lewy bodies are the histopathologic characteristics of neurodegenerative disorders and are protein-rich intracellular deposits in which Alpha-Synuclein is its major protein. Alpha-Synuclein's toxic potential provides a compelling rationale for therapeutic strategies aimed at decreasing its burden in neuronal cells through numerous pathways including ubiquitin-proteasome system and autophagy-lysosome Pathway, proteolytic breakdown via cathepsin D, kallikrein-6 (neurosin), calpain-1 or MMP9, heat shock proteins, and proteolysis targeting chimera which consists of a target protein ligand and an E3 ubiquitin ligase (E3) followed by target protein ubiquitination (PROTACs). Other targets that have been noticed recently are the mutant huntingtin, tau proteins and glycogen synthase kinase 3β that their accumulation proceeds extensive neuronal damage and up to the minute approach such as Proteolysis Targeting Chimera promotes its degradation in cells. As various studies demonstrated that Mendelian gene mutations can result into the neurodegenerative diseases, additional target that has gained much interest is epigenetics such as mutation, phosphodiesterase, RNA binding proteins and Nuclear respiratory factor 1. CONCLUSION The novel molecular targets and new strategies compiled and introduced here can be used by scientists to design and discover more efficient small molecule drugs against the neurodegenerative diseases. And also the genes in which their mutations can lead to the α-synuclein aggregation or accumulation are discussed and considered a valuable information of epigenetics in dementia.