The Interplay Between Autophagy and RNA Homeostasis: Implications for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Abstract

Amyotrophic lateral sclerosis and frontotemporal dementia are neurodegenerative disorders that lie on a disease spectrum, sharing genetic causes and pathology, and both without effective therapeutics. Two pathways that have been shown to play major roles in disease pathogenesis are autophagy and RNA homeostasis. Intriguingly, there is an increasing body of evidence suggesting a critical interplay between these pathways. Autophagy is a multi-stage process for bulk and selective clearance of malfunctional cellular components, with many layers of regulation. Although the majority of autophagy research focuses on protein degradation, it can also mediate RNA catabolism. ALS/FTD-associated proteins are involved in many stages of autophagy and autophagy-mediated RNA degradation, particularly converging on the clearance of persistent pathological stress granules. In this review, we will summarise the progress in understanding the autophagy-RNA homeostasis interplay and how that knowledge contributes to our understanding of the pathobiology of ALS/FTD.

Frontotemporal Dementia, Where Do We Stand? A Narrative Review

“…This neurodegenerative process is thought to originate in distinct regions and to spread within neural networks from cell to cell in a prion-like manner [81]. Several genetic hits (loss of function and toxic gain of function) contribute to alter proteostasis, boosting or sustaining vicious cycles that ultimately dysregulate pivotal cellular components (lysosome, mitochondria, and endoplasmic reticulum) or processes (autophagolysosomal trafficking, RNA homeostasis, endoplasmic reticulum-mitochondrial signalling, and axonal transport) and cause protein accumulation, sensitising cells to insult and finally leading to cell death [82][83][84][85][86]. Following the description of the molecular genetics of the three most common genetic causes, we will trace an overview of the key pathological mechanisms involved in FTD pathogenesis.…”

“…(1) loss of function of C9orf72 protein impairs synaptic vescicle recycling, causes lysosomal accumulation, alters glial secretomes (contributing to neuroinflammation), and affects autophagy-mediated RNA homeostasis [81][82][83]; (2) toxic gain of function of RNA foci: GGGGCC repeat RNAs form secondary structures (i.e., hairpins, stable G-quadruplexes, DNA-RNA heteroduplexes, and RNA duplexes), which affect promoter activity, genetic instability, RNA splicing, localisation, and transport system (through the sequestration of RNA-binding proteins) [81][82][83]85]; and (3) toxic gain of function of DRPs: arginine-rich DRPs have been shown to alter nucleocytoplasmic transport impacting neuronal survival as for RNA foci [81][82][83]85]. Interestingly, a strong interplay between three FTD-ALS-associated genes, C9orf72, TBK1, and TARDBP, was recently found: TBK1 is phosphorylated in response to C9orf72 poly(gly-ala) aggregation and sequestered into inclusions, resulting in decreased TBK1 activity and contributing to neurodegeneration.…”

The autophagy of stress granules

“…In terms of the mechanics of granulophagy, three broad mechanisms for the engulfment of SGs have either been hypothesised in the literature or can be extrapolated from new findings regarding the mode of engulfment of other autophagic cargo. These are engulfment of SGs whole, which is the mechanism most often depicted in diagrams of granulophagy [15,47,79,80], and has been demonstrated to occur in the autophagy of p62 gels [76,77]; piecemeal engulfment involving the budding off and sequestration of portions of granules, which has also been shown to occur in the case of p62 droplets [77]; or engulfment of SGs via finger-like projections of autophagosomal membrane, which has recently been proposed to be the major mechanism for engulfment of autophagic cargo [8] (Fig. 1).…”

Janus kinase inhibitors are potential therapeutics for amyotrophic lateral sclerosis

“…The cytoplasmic aggregates so formed may also sequester RNA transport components essential for appropriate export of RNA from the nucleus [ 82 ] and along the axon [ 83 ]. The stress granules may be causative in the generation of the toxic protein aggregates [ 84 ], so restoration of normal autophagic clearance of stress granules [ 85 ] would seem a necessary requirement in therapy.…”