Abstract
Cells robustly reprogram gene expression during stress generated by protein misfolding and aggregation. In this condition, cells assemble the bulk of mRNAs into translationally silent stress granules (SGs), while they sustain the translation of specific mRNAs coding for proteins that are needed to overcome cellular stress. Alterations of this process are deeply associated to neurodegeneration. This is the case of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder caused by a selective loss of motor neurons. Indeed, impairment of protein homeostasis as well as alterations of RNA metabolism are now recognized as major players in the pathogenesis of ALS. In particular, evidence shows that defective mRNA transport and translation are implicated. Here, we provide a review of what is currently known about altered mRNA translation in ALS and how this impacts on the ability of affected cells to cope with proteotoxic stress.
Highlights
Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disease
An early and specific induction of endoplasmic reticulum (ER) stress has been proposed to explain the selective vulnerability of motor neurons (Ng et al, 2015; Sun et al, 2015), suggesting that these alterations might play a key role in disease pathogenesis
This conclusion is further supported by the evidence that a number of genes that participate to the autophagic and proteasomal control of protein degradation, such as ubiquilin-2 (Deng et al, 2011), sequestosome-1 (Fecto et al, 2011), optineurin (Maruyama et al, 2010), valosin-containing protein (VCP; Johnson et al, 2010), TBK1 (Freischmidt et al, 2015) and VAPB (Chen et al, 2010), are associated to amyotrophic lateral sclerosis (ALS)
Summary
Cells robustly reprogram gene expression during stress generated by protein misfolding and aggregation. In this condition, cells assemble the bulk of mRNAs into translationally silent stress granules (SGs), while they sustain the translation of specific mRNAs coding for proteins that are needed to overcome cellular stress. Cells assemble the bulk of mRNAs into translationally silent stress granules (SGs), while they sustain the translation of specific mRNAs coding for proteins that are needed to overcome cellular stress Alterations of this process are deeply associated to neurodegeneration. We provide a review of what is currently known about altered mRNA translation in ALS and how this impacts on the ability of affected cells to cope with proteotoxic stress.
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