Russo A, Scardigli R, La Regina F, Murray ME, Romano N, Dickson DW, Wolozin B, Cattaneo A, Ceci M. Increased cytoplasmic TDP-43 reduces global protein synthesis by interacting with RACK1 on polyribosomes. Hum Mol Genet. 2017 Apr 15;26(8):1407-1418. PubMed.
Recommends
Please login to recommend the paper.
Comments
St. Jude Children's Research Hospital
Many if not all aspects of RNA metabolism take place in the setting of higher order, dynamic assemblies that arise through phase transitions. In the past year we have learned that low-complexity sequence domains (LCDs) in RNA-binding proteins (such as TDP-43, hnRNPA1 and FUS) participate in building these assemblies (Molliex et al., 2015; Lin et al., 2015; Patel et al., 2015). Indeed, this is likely essential to the influence exerted by RNA-binding proteins on RNA utilization and metabolism. The function of these LCDs is altered by disease-causing mutations. In the best documented cases, the mutations reduce the dynamism of the assemblies and promote fibrillization (Molliex et al., 2015; Patel et al, 2015; Murakami et al., 2015; Conicella et al., 2016). Importantly, an adverse consequence of poly-dipeptides produced from mutant C9ORF72 is to interact with LCDs and reduce dynamism, resulting in the same consequence as mutations in the LCDs themselves (Lee et al., 2016). These discoveries are at the core of the hypothesis that a primary driver of ALS is altered dynamics of higher-order assemblies composed of RNA-binding proteins such as TDP-43, hnRNPA1 and FUS. Our proposed mechanism is that the biology that normally takes place within higher-order mRNP assemblies is impaired at multiple levels, including translation, and simultaneously promotes the assembly of stable TDP-43 fibrils. It naturally follows that we will find modifiers of toxicity among the constituents of these higher-order assemblies, particularly among the direct interactome of TDP-43. Thus, this paper reveals further detail that is to be expected by our proposed hypothesis.
References:
Molliex A, Temirov J, Lee J, Coughlin M, Kanagaraj AP, Kim HJ, Mittag T, Taylor JP. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell. 2015 Sep 24;163(1):123-33. PubMed.
Lin Y, Protter DS, Rosen MK, Parker R. Formation and Maturation of Phase-Separated Liquid Droplets by RNA-Binding Proteins. Mol Cell. 2015 Oct 15;60(2):208-19. Epub 2015 Sep 24 PubMed.
Patel A, Lee HO, Jawerth L, Maharana S, Jahnel M, Hein MY, Stoynov S, Mahamid J, Saha S, Franzmann TM, Pozniakovski A, Poser I, Maghelli N, Royer LA, Weigert M, Myers EW, Grill S, Drechsel D, Hyman AA, Alberti S. A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation. Cell. 2015 Aug 27;162(5):1066-77. PubMed.
Murakami T, Qamar S, Lin JQ, Schierle GS, Rees E, Miyashita A, Costa AR, Dodd RB, Chan FT, Michel CH, Kronenberg-Versteeg D, Li Y, Yang SP, Wakutani Y, Meadows W, Ferry RR, Dong L, Tartaglia GG, Favrin G, Lin WL, Dickson DW, Zhen M, Ron D, Schmitt-Ulms G, Fraser PE, Shneider NA, Holt C, Vendruscolo M, Kaminski CF, St George-Hyslop P. ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function. Neuron. 2015 Nov 18;88(4):678-90. Epub 2015 Oct 29 PubMed.
Conicella AE, Zerze GH, Mittal J, Fawzi NL. ALS Mutations Disrupt Phase Separation Mediated by α-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain. Structure. 2016 Sep 6;24(9):1537-49. Epub 2016 Aug 18 PubMed.
Lee KH, Zhang P, Kim HJ, Mitrea DM, Sarkar M, Freibaum BD, Cika J, Coughlin M, Messing J, Molliex A, Maxwell BA, Kim NC, Temirov J, Moore J, Kolaitis RM, Shaw TI, Bai B, Peng J, Kriwacki RW, Taylor JP. C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles. Cell. 2016 Oct 20;167(3):774-788.e17. PubMed.
View all comments by J. Paul TaylorBoston University School of Medicine
The article by Marcello Ceci’s group provides an important advance in our understanding of the biology of TDP-43. The mechanisms of aggregation of TDP-43 are clearly important for understanding the pathophysiology of ALS, but such understanding is always informed by a broader understanding of the biology of the protein. In the current manuscript (of which I am a co-author), Marcello’s group has elegantly demonstrated that TDP-43 interacts with the ribosome, and that this interaction is mediated by RACK1. The manuscript demonstrates this interaction using multiple independent approaches, but I think one of the most powerful approaches is Marcello’s use of ribosomal profiling, which fractionates ribosomal proteins and allows investigation of the biochemical association of TDP-43 with the ribosome, which occurs through the interaction with RACK1. An important caveat for this work is the need to examine the results using gene deletion rather than overexpression. Nonetheless, these results are important because many RNA binding proteins are known to regulate translation, but the role played by TDP-43 in translation is poorly understood. The current manuscript clearly demonstrates a strong potential for a generalized role of TDP-43 in translation.
The field has been captivated by the potential role that RNA granules, particularly (but not exclusively) stress granules, might play in the pathophysiology of ALS (Kedersha and Anderson, 2007; Protter and Parker, 2016). RNA binding proteins, such as TDP-43, control the localization and utilization of RNA through a process of “reversible aggregation”, which can sequester particular RNA binding proteins and associated transcripts and thereby regulate their translation (Ash et al., 2014; Liu-Yesucevitz et al., 2010; Johnson et al., 2009; Kim et al., 2013). The biology of these proteins is exemplified in studies using recombinant proteins, where the biophysical properties of individual proteins are highlighted. This process is termed liquid-liquid phase separation (LLPS) (Lin et al., 2015; Molliex et al., 2015; Patel et al., 2015; Murakami et al., 2015). These studies also show the tendency this LLPS process to go awry and irreversibly form amyloids. This process is thought to contribute to disease, but much work remains to be done before we fully understand the extent to which LLPS contributes to human disease.
A meaningful translation to disease is to look for clues in the pathological specimens. The current study by Ceci and colleagues makes an important contribution to our understanding of disease by showing that RACK1 associates with ALS pathology in the spinal cord of patients with ALS, and also showing that other stress granule proteins, such as PABPC, are associated with TDP-43 pathology. Thus, there clearly is some pathological connection between all of these proteins. Taken together, this work provides a significant advance in our understanding of the basic biology of TDP-43, and also supports a role for RNA granules/stress granules in the pathophysiology of ALS.
References:
Kedersha N, Anderson P. Mammalian stress granules and processing bodies. Methods Enzymol. 2007;431:61-81. PubMed.
Protter DS, Parker R. Principles and Properties of Stress Granules. Trends Cell Biol. 2016 Sep;26(9):668-79. Epub 2016 Jun 9 PubMed.
Ash PE, Vanderweyde TE, Youmans KL, Apicco DJ, Wolozin B. Pathological stress granules in Alzheimer's disease. Brain Res. 2014 Oct 10;1584:52-8. Epub 2014 Aug 7 PubMed.
Liu-Yesucevitz L, Bilgutay A, Zhang YJ, Vanderweyde T, Vanderwyde T, Citro A, Mehta T, Zaarur N, McKee A, Bowser R, Sherman M, Petrucelli L, Wolozin B. Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. PLoS One. 2010;5(10):e13250. PubMed.
Johnson BS, Snead D, Lee JJ, McCaffery JM, Shorter J, Gitler AD. TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J Biol Chem. 2009 Jul 24;284(30):20329-39. Epub 2009 May 22 PubMed.
Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, Maclea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature. 2013 Mar 28;495(7442):467-73. PubMed.
Lin Y, Protter DS, Rosen MK, Parker R. Formation and Maturation of Phase-Separated Liquid Droplets by RNA-Binding Proteins. Mol Cell. 2015 Oct 15;60(2):208-19. Epub 2015 Sep 24 PubMed.
Molliex A, Temirov J, Lee J, Coughlin M, Kanagaraj AP, Kim HJ, Mittag T, Taylor JP. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell. 2015 Sep 24;163(1):123-33. PubMed.
Patel A, Lee HO, Jawerth L, Maharana S, Jahnel M, Hein MY, Stoynov S, Mahamid J, Saha S, Franzmann TM, Pozniakovski A, Poser I, Maghelli N, Royer LA, Weigert M, Myers EW, Grill S, Drechsel D, Hyman AA, Alberti S. A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation. Cell. 2015 Aug 27;162(5):1066-77. PubMed.
Murakami T, Qamar S, Lin JQ, Schierle GS, Rees E, Miyashita A, Costa AR, Dodd RB, Chan FT, Michel CH, Kronenberg-Versteeg D, Li Y, Yang SP, Wakutani Y, Meadows W, Ferry RR, Dong L, Tartaglia GG, Favrin G, Lin WL, Dickson DW, Zhen M, Ron D, Schmitt-Ulms G, Fraser PE, Shneider NA, Holt C, Vendruscolo M, Kaminski CF, St George-Hyslop P. ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function. Neuron. 2015 Nov 18;88(4):678-90. Epub 2015 Oct 29 PubMed.
View all comments by Benjamin WolozinMake a Comment
To make a comment you must login or register.