18 Oct 2022

Amyotrophic lateral sclerosis and frontotemporal dementia may seem like different diseases, but they are often marked by the same pathology, namely, cytoplasmic inclusions of TDP-43. Hexanucleotide expansions in the C9ORF72 gene, or, more rarely, loss-of-function variants in the gene for TANK-binding kinase 1 (TBK1), can cause either disease. Now, a study published October 7 in Science reports that the products of these two genes are in cahoots. Scientists led by Leonard Petrucelli and Yong-Jie Zhang of the Mayo Clinic in Jacksonville, Florida, found that poly-GA inclusions translated from the C9ORF72 expansions ensnare TBK1, putting the kibosh on endolysosomal transport. This leaves TDP-43 adrift in the cytoplasm, where it aggregates. All these problems become drastically worse when TBK1 harbors a loss-of-function mutation. The findings place C9ORF72, TBK1, and TDP-43 in the same functional pathway, and implicate endolysosomal malfunction as a central disease mechanism in ALS/FTD.

Hexanucleotide expansions in C9ORF72 are the most common genetic cause of ALS/FTD, but exactly how the expansions lead to TDP-43 aggregation has puzzled scientists. In addition to hobbling normal expression of the C9 gene, the expansions are transcribed into troublesome RNA foci and translated into poly dipeptide repeats (DPRs) that aggregate within neurons (Aug 2018 news; Nov 2018 conference news). TDP-43 pathology in ALS/FTD also associates with loss-of-function variants in TBK1, a kinase involved in autophagy, as well as endosomal function (Hao et al., 2021). How these mutations dovetail with TDP-43 pathology is also unclear.

Both causal and risk variants have been identified for TBK1, and some studies have suggested that some of these require a “second hit” to trigger disease. In cases where that comes from C9ORF72 expansions, carriers tend to suffer from an earlier onset, more rapidly worsening disease than do people who carry either mutation alone (Mossevelde et al., 2016). Do variants in these two genes conspire to hasten TDP-43 pathology and disease?

To find out, first author Wei Shao and colleagues first examined if C9ORF72 expansions influence wild-type TBK1. In mice infected with an adeno-associated virus expressing C9ORF72 repeat expansions, they spotted TBK1 mingling with DPRs within neurons. The researchers pegged a specific DPR—poly-GA—with coaxing TBK1 into these aggregates, where it then phosphorylated itself. Although this autophosphorylation is known to activate TBK1, the researchers proposed that entrapment of the kinase would limit its functions. Chief among them is phosphorylation of p62, a ubiquitin receptor that delivers proteins to autophagosomes. Without an active TBKI, a slowdown in autophagic flux would further exacerbate the accumulation of poly-GA aggregates, feeding a vicious cycle, the authors surmised. Another ALS/FTD gene, SQSTM1, codes for p62, aka sequestosome 1 (Nov 2011 conference news). 

In keeping with this idea, when the scientists overexpressed normal TBK1 in cells burdened by poly-GA aggregates, p62 phosphorylation increased and poly-GA aggregates fell. Not so if Shao overexpressed R228H-TBK1, a partial-loss-of-function variant linked to ALS. This defunct version failed to rouse autophagy or help clear poly-GA aggregates. In mice, the R228H variant exacerbated all phenotypes of poly-GA aggregation, including accumulation of poly-GA itself, neuroinflammation, neurodegeneration, and problems with balance and memory. Tellingly, TDP-43 aggregation doubled, suggesting properly functioning TBK1 kinase is critical for keeping this pathology at bay.

What happens when the kinase falters? Through a series of cell culture and mouse experiments, the researchers pieced together a cascade in which TBK1 loss of function—caused by mutation or by poly-GA entrapment—derails endolysosomal function (see diagram below). This then somehow instigates TDP-43 pathology, they proposed. In support of this idea, they also found that merely blocking the maturation of endosomes led TDP-43 to accumulate within the cytoplasm.

In all, the findings place endolysosomal traffic jams at the heart of ALS-FTD pathogenesis, suggested Jean-Marc Gallo of King’s College London and Dieter Edbauer of the German Center for Neurodegenerative Diseases, Munich, in an accompanying Science Perspective. In further support of this idea, other ALS/FTD genes, including progranulin and TMEM106b, are also involved in similar pathways. Furthermore, an autophagic slowdown caused by C9ORF72 loss of function has been tied to neuroinflammation and toxic aggregation (Nov 2018 conference news; McCauley et al., 2020).

Still, mechanistic mysteries remain. “How impaired endosome maturation leads to the formation of TDP-43 inclusions in the cytoplasm and nuclear depletion, whatever comes first, are still important out­standing questions,” Gallo and Edbauer wrote.

The findings could have implications for other neurodegenerative diseases, too. Zhang and Petrucelli suggested that due to its penchant for binding to protein polymers, TBK1 may mingle with aggregates found in other proteinopathies (see Q&A below). “It will be interesting to examine the co-localization of TBK1 with other disease-associated protein aggregates such as tau, α-synuclein, and TDP-43 in human tissue and disease-relevant mouse models,” they wrote. “A comprehensive survey of which disease-relevant aggregates associate with TBK1 would not only allow us to determine whether TBK1 has a broad role in multiple neurogenerative diseases, but also provide a deeper understanding of what kinds of protein polymer structures are essential for interacting with and potentially sequestering TBK1,” they wrote.—Jessica Shugart

 

Q&A with Leonard Petrucelli and Yong-Jie Zhang. Questions by Jessica Shugart

Q: The sequestration of TBK1 inhibited its functions, including promoting autophagic clearance of aggregates. This, in turn, exacerbated accumulation of poly-GA aggregates. Could C9ORF72 loss of function also contribute to this autophagy deficit in ALS/FTD?

A: This is a great point. Loss of the C9ORF72 protein impairs the autophagy-lysosome pathway (Smeyers et al., 2021)—and this does indeed lead to an increase in abnormal protein aggregation, including enhanced accumulation of poly-GA (Zhu et al., 2020). Accordingly, we believe that C9ORF72 coordinates with TBK1 in the regulation of the endolysosomal pathway and protein clearance, and that the loss of both of these factors can impact protein aggregation (e.g., poly-GA and TDP-43), as well as neurodegeneration, in c9FTD/ALS. Investigating the combinatorial effects of C9orf72 and TBK1 loss of function in c9FTD/ALS pathogenesis is one of our future directions.

Q: Might other types of aggregates, found in different forms of neurodegenerative disease, also interact with and sequester TBK1?

A: This is also a great question. We believe that it is quite possible that other types of protein aggregates, found in different forms of neurodegenerative disease, also interact with, and sequester, TBK1. As shown in our current paper, the interaction of TBK1 and poly-GA is dependent upon poly-GA aggregation. Our finding is consistent with previous reports showing TBK1 binds to protein polymers. For example, short double-stranded DNA in the cytosol triggers the DNA sensor cGAS, which then promotes STING polymerization. TBK1 concentrates on STING polymers (Tu et al., 2013; Zhang et al., 2019). 

It will be interesting to examine the co-localization of TBK1 with other disease-associated protein aggregates such as tau, α-synuclein and TDP-43 in human tissue and disease-relevant mouse models. It is worth noting that TBK1 interacts with poly-GA but not with poly-GR, suggesting the structure of the protein aggregates is also important for the interaction. A comprehensive survey of which disease-relevant aggregates associate with TBK1 would therefore allow us to not only determine whether TBK1 has a broad role in multiple neurogenerative diseases, but also provide a deeper understanding of what kinds of protein polymer structures are essential for interacting with and potentially sequestering TBK1.

Q: TBK1 is involved in autophagy as well as endosomal maturation. How are these two TBK1-related pathways connected, and how do you think each contributes to pathogenesis? To what extent do you think the slowing of autophagy versus the problems with endosomal maturation contribute to neurodegeneration in ALS/FTD?

A: This is an important question, and the answer will be critical to our understanding of the disease pathogenesis. TBK1 modulates both endosome maturation and the efficiency of autophagic adaptors (i.e., p62, and optineurin), implicating it in both the endolysosomal pathway and autophagic clearance. These two TBK1-related pathways are intrinsically connected—proper endosome maturation is essential for the development of autolysosomes, and autophagic adaptors are needed for the proper targeting of cargo into these degradative compartments. Exactly how each of these pathways influence neurodegeneration is still under investigation, and we are exploring multiple hypotheses.

For instance, our current study raises the following possible scenario: poly-GA aggregates sequester TBK1, impairing its ability to regulate endosome maturation and inducing early endosomal defects which could negatively impact downstream lysosome biogenesis and amphisome formation. At the same time, the sequestration of TBK1 also compromises the activity of its autophagy adaptor targets, reducing their ability to recognize cargoes and ultimately enhancing the accumulation of protein aggregates—including poly-GA. This creates a negative feedback loop that keeps TBK1 sequestered and continues to dampen its activity in both pathways. Interestingly, evidence suggests that, in addition to TBK1, C9ORF72 also regulates both the endosomal and autophagy pathways (Smeyers et al., 2021). Specifically, C9ORF72 regulates endosomal recycling, while it influences autophagy at multiple stages, including initiation, maturation, and substrate degradation. This adds another wrinkle to the story, because both pathways could be further impaired by C9orf72 loss of function in c9FTD/ALS.

Overall, given how tightly regulated the endosomal and autophagic pathways are connected, it may be difficult to discriminate the extent to which each individual pathway contributes to neurodegeneration in FTD/ALS. Recent studies suggest that inhibiting autophagy alone is insufficient to induce TDP-43 proteinopathy in human motor neurons (Hao et al., 2021), while preventing lysosome acidification (Hao et al., 2021) or impairing endosomal maturation [our study] does lead to the development of TDP-43 aggregates. This data suggests that the endolysosomal pathway could be critical for TDP-43 homeostasis, but TDP-43 is just one part of the puzzle. Ultimately both pathways could be key players in disease and further interrogated.

Q: What does this study tell us about the central mechanisms involved in ALS/FTD? Does it suggest the possibility of common therapeutic targets across different forms of these diseases?

A: Our study reveals that the oligogenic effects of C9orf72 and TBK1 converge on the endolysosomal pathway, and that the induction of endosomal defects could be a key step in a pathological cascade. While our work focuses on C9orf72 and TBK1, several other FTD/ALS-linked genes—including ALS2, FIG4, VCP, CHMP2B, GRN, and TMEM106B—are all related to the endolysosomal system at different stages (Varga et al., 2015; Kunita et al., 2004; Chow et al., 2007; Skibinski et al., 2005; Chang et al., 2022; Schweighauser et al., 2022; Jiang et al., 2022). Thus, the disruption of this pathway could be a point of convergence between various pathological factors. In fact, our study suggests that the disruption of this pathway alone could be a driving factor in the development of TDP-43 pathology, even in the absence of known genetic lesions.

While we think the endolysosomal pathway is a central pathway in disease, and that factors involved in this pathway could represent common therapeutic targets across different forms of FTD/ALS, we also acknowledge that further studies are warranted to support this hypothesis. We still need to confirm whether defects in the endolysosomal pathway are observed in sporadic FTD/ALS patients, and we are actively determining whether the pathway is indeed crucial for maintaining TDP-43 homeostasis in vivo.

Comments

1. • Brian Freibaum
     
   • Posted: 19 Oct 2022

   This is an exciting publication that establishes both temporal and mechanistic linkages between three ALS proteins: glycine-alanine poly-dipeptide repeats, TBK1, and TDP-43. I am curious as to how the endosomal defects are inducing TDP-43 pathology in neurons. Regarding the central mechanism at play in ALS/FTD, I believe that this paper further confirms that there may not be a single central mechanism, but rather a convergence of defects in multiple pathways.

   View all comments by Brian Freibaum
2. • Johnathan Cooper-Knock
     University of Sheffield
   • Posted: 19 Oct 2022

   Here, Shao et al. have performed a series of studies based on the observation that ALS-associated TBK1 loss-of-function mutations are observed to associate with G4C2-repeat expansions in C9ORF72 in a small number of patients, but with a measurable effect on the clinical phenotype. The authors use this association to design experiments to uncover the important mechanisms driving disease.

   The authors observed aggregation of phosphorylated (active) TBK1 in model systems expressing expanded C9ORF72, and even within cells in the cortices of C9ORF72-FTD-ALS patients. This was reproduced by overexpression of poly-GA dipeptide repeat protein in vitro, while overexpression of wild-type, but not R228H-TBK1, reduced poly-GA aggregation. R228H-TBK1 is an important disease-associated mutation.

   Of the five dipeptide repeat proteins (DPRs) transcribed from the C9ORF72 repeat expansion, poly-GA has previously been dismissed as less relevant to neurotoxicity, so it is interesting to see it at the center of this study. Poly-GA is the most abundant DPR in postmortem material, including within disease-relevant tissues such as the frontal cortex (Zhang et al., 2014). However, studies of disease models have often concluded that the relative toxicity of arginine-rich DPRs is greater than poly-GA (e.g., Mizielinska et al., 2014). Importantly, only poly-GR has been correlated with TDP-43 pathology in patient tissue (Saberi et al., 2018). A mechanistic convergence between Poly-GA and another ALS risk gene adds significant weight to the idea that this protein is an important driver of pathogenesis.

   The authors delve deeper into the underlying mechanism. Loss of TBK1 impairs endosome maturation. Here the authors showed that expression of poly-GA in mice had a similar effect, leading to higher numbers of abnormal endosomes; importantly, endosome phenotypes were observed within cells expressing poly-GA and were exacerbated by a background of R228H-TBK1 expression, as opposed to wild-type TBK1. Crucially, cells expressing poly-GA that had endosome abnormalities also shunted TDP-43 from the nucleus into cytoplasmic inclusions, which are a hallmark pathology of ALS and FTD.

   These observations are interesting, and the suggestion that poly-GA and TBK1 may be linked to TDP-43 mis-localization places them at the heart of pathogenesis. Mis-localization of nuclear TDP-43 is a key step in disease pathogenesis, as we learned earlier this year from two works demonstrating a direct link between loss of nuclear TDP-43, reduced expression of UNC13A, and ALS clinical severity (Brown et al., 2022; Ma et al., 2022). 

   To complete the circle, the authors attempted to show that endosomal defects were sufficient, in isolation, to cause TDP-43 mis-localization but here they came up short. Endogenous TDP-43 was not mis-localized from the nucleus by a Rab5-Q79L mutation, which impaired endosome maturation in vitro. There was, however, some evidence of TDP-43 aggregation in this model system which, as the authors point out, might eventually seed mis-localization of nuclear TDP-43.

   References:

   Zhang YJ, Jansen-West K, Xu YF, Gendron TF, Bieniek KF, Lin WL, Sasaguri H, Caulfield T, Hubbard J, Daughrity L, Chew J, Belzil VV, Prudencio M, Stankowski JN, Castanedes-Casey M, Whitelaw E, Ash PE, DeTure M, Rademakers R, Boylan KB, Dickson DW, Petrucelli L. Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol. 2014 Oct;128(4):505-24. Epub 2014 Aug 31 PubMed.

   Mizielinska S, Grönke S, Niccoli T, Ridler CE, Clayton EL, Devoy A, Moens T, Norona FE, Woollacott IO, Pietrzyk J, Cleverley K, Nicoll AJ, Pickering-Brown S, Dols J, Cabecinha M, Hendrich O, Fratta P, Fisher EM, Partridge L, Isaacs AM. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science. 2014 Sep 5;345(6201):1192-1194. Epub 2014 Aug 7 PubMed.

   Saberi S, Stauffer JE, Jiang J, Garcia SD, Taylor AE, Schulte D, Ohkubo T, Schloffman CL, Maldonado M, Baughn M, Rodriguez MJ, Pizzo D, Cleveland D, Ravits J. Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis. Acta Neuropathol. 2018 Mar;135(3):459-474. Epub 2017 Dec 1 PubMed.

   Brown AL, Wilkins OG, Keuss MJ, Hill SE, Zanovello M, Lee WC, Bampton A, Lee FC, Masino L, Qi YA, Bryce-Smith S, Gatt A, Hallegger M, Fagegaltier D, Phatnani H, NYGC ALS Consortium, Newcombe J, Gustavsson EK, Seddighi S, Reyes JF, Coon SL, Ramos D, Schiavo G, Fisher EM, Raj T, Secrier M, Lashley T, Ule J, Buratti E, Humphrey J, Ward ME, Fratta P. TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. Nature. 2022 Mar;603(7899):131-137. Epub 2022 Feb 23 PubMed. Correction.

   Ma XR, Prudencio M, Koike Y, Vatsavayai SC, Kim G, Harbinski F, Briner A, Rodriguez CM, Guo C, Akiyama T, Schmidt HB, Cummings BB, Wyatt DW, Kurylo K, Miller G, Mekhoubad S, Sallee N, Mekonnen G, Ganser L, Rubien JD, Jansen-West K, Cook CN, Pickles S, Oskarsson B, Graff-Radford NR, Boeve BF, Knopman DS, Petersen RC, Dickson DW, Shorter J, Myong S, Green EM, Seeley WW, Petrucelli L, Gitler AD. TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A. Nature. 2022 Mar;603(7899):124-130. Epub 2022 Feb 23 PubMed.

   View all comments by Johnathan Cooper-Knock
3. • Jochen Weishaupt
     Heidelberg University
   • Posted: 22 Oct 2022

   This paper is certainly interesting, suggesting an additional mechanism by which TBK1 deficiency can occur, other than through loss-of-function mutations. On the other hand, I find it somewhat preliminary to draw a direct conclusion with regard to ALS. The activity, or at least the amount of TBK1 protein, has not been studied in tissue from C9ORF72 mutation carriers. Moreover, the missense mutation used in the paper is of uncertain significance for ALS causation. It would be informative to use one of the TBK1 KO mouse lines or a TBK1 missense mutation with proven pathogenicity.

   It remains also unclear why motor-neuron-specific TBK1 deletion does not lead to any signs of neurodegeneration in mice (Gerbino et al., 2020), considering the present study's hypothesis that poly(GA) inclusions sequester TBK1, thus reduce its function, which then disrupts endosome maturation and induces TDP-43 aggregation. Maybe the toxicity is linked directly to poly(GA) inclusions, and sequestering TBK1 simply accelerates this?

   References:

   Gerbino V, Kaunga E, Ye J, Canzio D, O'Keeffe S, Rudnick ND, Guarnieri P, Lutz CM, Maniatis T. The Loss of TBK1 Kinase Activity in Motor Neurons or in All Cell Types Differentially Impacts ALS Disease Progression in SOD1 Mice. Neuron. 2020 Jun 3;106(5):789-805.e5. Epub 2020 Mar 27 PubMed.

   View all comments by Jochen Weishaupt

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References

News Citations

1. In C9ORF72 Expansion Carriers, Protein Levels Drop in Cerebellum 17 Aug 2018
2. DC: Protein Work Expands ALS/FTD Genetics 25 Nov 2011
3. It’s ‘And,’ Not ‘Either-Or’: C9ORF72 Mechanisms of Action are Linked 30 Nov 2018

Paper Citations

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Other Citations

1. Nov 2018 conference news

Further Reading

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