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Shao W, Todd TW, Wu Y, Jones CY, Tong J, Jansen-West K, Daughrity LM, Park J, Koike Y, Kurti A, Yue M, Castanedes-Casey M, Del Rosso G, Dunmore JA, Zanetti Alepuz D, Oskarsson B, Dickson DW, Cook CN, Prudencio M, Gendron TF, Fryer JD, Zhang YJ, Petrucelli L. Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration. Science. 2022 Oct 7;378(6615):94-99. Epub 2022 Oct 6 PubMed.
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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 FreibaumUniversity of Sheffield
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-KnockHeidelberg University
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 WeishauptMake a Comment
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