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Review
. 2022 Apr 28:10:838402.
doi: 10.3389/fcell.2022.838402. eCollection 2022.

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

O H Houghton  1   2 , S Mizielinska  1   2 , P Gomez-Suaga  1   3   4   5
Affiliations
Review

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

O H Houghton et al. Front Cell Dev Biol. .

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.

Keywords: C9orf72; RNA; RNA-binding proteins; amyotrophic lateral sclerosis; autophagy; frontotemporal dementia; granulophagy; stress granules.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The stages of macroautophagy (autophagy). Autophagy initiation is tightly regulated commonly by two well-known kinases, mTORC1 and AMPK1, which inhibit or promote the activity of the ULK1 complex respectively. The ULK1 complex, consisting of ULK1, ATG13, FIP200 and ATG101, translocates to the autophagosome formation site with the transmembrane spanning ATG9 to stimulate nucleation of the phagophore membrane. The ULK1 complex activates the PI3K complex class III, formed of VSP34, VSP15, Beclin1 and ATG14, resulting in the production of PI3P and recruitment of proteins with PI3P-binding domains. The phagophore elongates, sequestering autophagic cargo for degradation. This elongation process is regulated by two ubiquitin-like reactions, the ATG12/ATG5–ATG16L1 complex formation and the conjugation of LC3 to the lipid anchor PE to form LC3-II, facilitated by ATG7 and other proteins. ESCRT proteins enable the elongation and fusing of phagophore edges to form the autophagosome which can undergo further maturation through fusion with endocytic vesicles to form amphisomes. Motor proteins, RAB GTPases and SNAREs facilitate the fusion of autophagosomes/amphisomes with lysosomes to form autolysosomes, within which cargo is degraded into metabolites and released for cellular recycling.
FIGURE 2
FIGURE 2
Autophagy-dependent RNA homeostasis. Autophagy-dependent RNA catabolism involves the degradation of RNA, RNA-binding proteins and RNA granules within the lysosomal lumen by RNases such as RNase T2 and lysosomal acidic hydrolases. Through RNautophagy, mRNA molecules are taken up directly into the lysosome through SIDT2 or LAMP2 proteins, in an ATP-dependent manner. Unbound RNA can also directly interact with LC3 via its arginine-rich motif however the impact of this requires further investigation. Ribophagy is a mechanism for autophagy dependent ribosome clearance by which ribosomes are engulfed within the autophagosome and delivered to the lysosome for degradation. mRNA can associate with RNA-binding proteins and accumulate in dynamic RNA granules such as stress granules (SG) or P-bodies (PB). Granulophagy is the process by which SGs are recruited for selective autophagy, which may involve the protein VCP. An additional mechanism of SG recruitment has been proposed, by which the PRMT5-dependent symmetric arginine methylation of SG components, such as FUS, allows for their recognition by the p62/C9orf72 complex via the SMN protein. Autophagy-dependent RNA catabolism is also impacted by the transport and secretion of RNA/RNA complexes. RNA transport involves SGs and other RNA complexes hitchhiking on motile vesicles, a process that involves the docking of RNA granules via molecular tethers. Notably, the ALS-associated RBP Annexin A11 is a component of SGs and can also bind lysosomes that are transported along microtubules. The autophagy machinery is also involved in the non-canonical autophagy function of secretory autophagy. By this process, the contents of autophagosomes, which may contain RNA and RBPs, bypass degradation and instead are directly secreted from the cell.
FIGURE 3
FIGURE 3
The role of ALS/FTD-associated genes in autophagy-dependent RNA catabolism. Several stages of the autophagy pathway, in addition to selective autophagic degradation of stress granules, are affected by ALS/FTD-linked gene (green) products, some of which are RBPs that transcriptionally and/or post-transcriptionally regulate autophagy-related proteins (purple). Autophagy initiation is transcriptionally regulated by TFEB, AMPK and FOXO which can be affected by C9orf72 protein and repeat RNA/DPRs, TBK1 and TDP43 (TARDBP), respectively. TFEB activity is modulated by mTORC1 which is also regulated by C9orf72 and TDP43 proteins. C9orf72, VAPB, VCP and FUS proteins play roles in different stages of autophagosome formation. Proteins participating in autophagosome formation are also post-transcriptionally regulated by TDP43, FUS and hnRNPA1 proteins. Selective SG degradation - termed granulophagy - can be mediated by C9orf72, p62 (SQSTM1), SMN, TBK1 and VCP proteins. CHMP2B, FIG4, ALS2 and the C9orf72 protein participate in the maturation of autophagosomes to form amphisomes in the intersection with the endocytic pathway. SIGMAR1, CCNF and TBK1 gene products are required for appropriate autophagosome-lysosome membrane fusion. Retrograde transport of autophagic structures contributes to proper autophagy flux and it is affected by ALS/FTD-linked PFN1, TUBA4A, KIF5A, DCTN1 and SPG11 genes, coding for proteins of the vesicle transport machinery. Likewise, the C9orf72 protein is proposed to contribute vesicular trafficking, and annexin A11 (ANXA11) plays a role in RNA granule-lysosomal trafficking. Appropriate lysosomal degradative capacity of autophagic cargo is affected by ALS/FTD-linked proteins encoded by C9orf72, GRN and UBQLN2. Finally, spatacsin (SPG11) is involved in lysosomal reformation.
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