Protein synthesis modulation as a therapeutic approach for amyotrophic lateral sclerosis and frontotemporal dementia

CHARIF, SANTIAGO ELÍAS; VASSALLU, MARÍA FLORENCIA; SALVAÑAL, LARA; MULLER IGAZ, LIONEL

NEURAL REGENERATION RESEARCH

SHENYANG EDITORIAL DEPT NEURAL REGENERATION RES

Año: 2021

1673-5374

alterations of protein content can lead to particular diseases. Cells have an intrinsic arrayof mechanisms and pathways that are activated when protein misfolding, accumulation,aggregation or mislocalization occur. Some of them (like the unfolded protein response)represent complex interactions between endoplasmic reticulum sensors and elongationfactors that tend to increase expression of chaperone proteins and/or repress translationin order to restore protein homeostasis (also known as proteostasis). This is even moreimportant in neurons, as they are very susceptible to harmful effects associated withprotein overload and proteostatic mechanisms are less effective with age. Severalneurodegenerative pathologies such as Alzheimer?s, Parkinson?s, and Huntington?sdiseases, amyotrophic lateral sclerosis and frontotemporal dementia exhibit a particularmolecular signature of distinct, unbalanced protein overload. In amyotrophic lateralsclerosis and frontotemporal dementia, the majority of cases present intracellularinclusions of ubiquitinated transactive response DNA-binding protein of 43 kDa (TDP-43). TDP-43 is a RNA binding protein that participates in RNA metabolism, amongother functions. Dysregulation of TDP-43 (e.g. aggregation and mislocalization) candramatically affect neurons, and this has been linked to disease development. Expressionof amyotrophic lateral sclerosis/frontotemporal dementia TDP-43-related mutationsin cellular and animal models has been shown to recapitulate key features of theamyotrophic lateral sclerosis/frontotemporal dementia disease spectrum. These variantscan be causative of degeneration onset and progression. Most neurodegenerative diseases(including amyotrophic lateral sclerosis and frontotemporal dementia) have no cure atthe moment; however, modulating translation has recently emerged as an attractiveapproach that can be performed at several steps (i.e. regulating activation of initiation andelongation factors, inhibiting unfolded protein response activation or inducing chaperoneexpression and activity). This review focuses on the features of protein imbalance inneurodegenerative disorders and the relevance of developing therapeutical compoundsaiming at restoring proteostasis. We strive to highlight the importance of research ondrugs that, not only restore protein imbalance without compromising translational activityof cells, but are also as safe as possible for the patients.