Zhang YJ, Gendron TF, Grima JC, Sasaguri H, Jansen-West K, Xu YF, Katzman RB, Gass J, Murray ME, Shinohara M, Lin WL, Garrett A, Stankowski JN, Daughrity L, Tong J, Perkerson EA, Yue M, Chew J, Castanedes-Casey M, Kurti A, Wang ZS, Liesinger AM, Baker JD, Jiang J, Lagier-Tourenne C, Edbauer D, Cleveland DW, Rademakers R, Boylan KB, Bu G, Link CD, Dickey CA, Rothstein JD, Dickson DW, Fryer JD, Petrucelli L. C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nat Neurosci. 2016 May;19(5):668-77. Epub 2016 Mar 21 PubMed.

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  1. Zhang et al. convincingly show that in mice, overexpression of polyGA causes neurodegeneration, which is dependent on the ability of polyGA to aggregate. The confirmation of polyGA toxicity in mice is an important step forward and will no doubt further fuel the current debate around the toxic species in C9ORF72-based FTD/ALS. Our work showed that polyGA is toxic to adult Drosophila neurons, but that it is much less potent than polyGR and polyPR (Mizielinska et al., 2014). This indicates that the levels of these proteins in patients will be an important factor. Therefore, while these new data show that polyGA can be toxic, they do not clarify which species is ultimately the toxic one in patients. That will require a better understanding of not only the levels of each species in patients but also their conformation; indeed, the authors here suggest polyGA oligomers may be the culprit.

    A powerful aspect of the study is the ability to compare polyGA toxicity to the Petrucelli lab’s pure repeat mouse model that utilizes the same AAV system but generates polyGA, polyGP, polyGR, and RNA foci (Chew et al., 2015). Importantly, TDP-43 pathology is much greater in the pure repeat mice, indicating that polyGA is not solely responsible for TDP-43 aggregation. It will be of great interest to determine whether expression of the other individual dipeptide repeat proteins (DPRs), such as polyGR and polyPR, lead to TDP-43 pathology. An intriguing possibility is that more than one DPR may be required for TDP-43 aggregation. It is also possible the RNA repeats rather than DPRs drive TDP-43 pathology. 

    Another intriguing aspect of the work is the identification of nuclear pore defects in polyGA mice. This is because work in Drosophila and yeast indicate that either polyGR/PR or repeat RNA are responsible for the nucleocytoplasmic defects identified in these model systems (Freibaum et al., 2015; Zhang et al., 2015; Jovicic et al., 2015; Boeynaems et al.,  2016). Further investigation of the specific effects of each species on nucleocytoplasmic transport should give new insight into this emerging pathway and its role in C9FTD/ALS.

    References:

    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.

    Chew J, Gendron TF, Prudencio M, Sasaguri H, Zhang YJ, Castanedes-Casey M, Lee CW, Jansen-West K, Kurti A, Murray ME, Bieniek KF, Bauer PO, Whitelaw EC, Rousseau L, Stankowski JN, Stetler C, Daughrity LM, Perkerson EA, Desaro P, Johnston A, Overstreet K, Edbauer D, Rademakers R, Boylan KB, Dickson DW, Fryer JD, Petrucelli L. Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science. 2015 Jun 5;348(6239):1151-4. Epub 2015 May 14 PubMed.

    Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC, Petrucelli L, Kim HJ, Gao FB, Taylor JP. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):129-33. Epub 2015 Aug 26 PubMed.

    Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):56-61. Epub 2015 Aug 26 PubMed.

    Jovičić A, Mertens J, Boeynaems S, Bogaert E, Chai N, Yamada SB, Paul JW 3rd, Sun S, Herdy JR, Bieri G, Kramer NJ, Gage FH, Van Den Bosch L, Robberecht W, Gitler AD. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci. 2015 Sep;18(9):1226-9. PubMed.

    Boeynaems S, Bogaert E, Michiels E, Gijselinck I, Sieben A, Jovičić A, De Baets G, Scheveneels W, Steyaert J, Cuijt I, Verstrepen KJ, Callaerts P, Rousseau F, Schymkowitz J, Cruts M, Van Broeckhoven C, Van Damme P, Gitler AD, Robberecht W, Van Den Bosch L. Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD. Sci Rep. 2016 Feb 12;6:20877. PubMed.

    View all comments by Adrian Isaacs

  2. This is an interesting study that adds further important insights to a series of findings that all point toward transport across the nuclear membrane as a process that is especially vulnerable not only in cells that encounter aggregation-prone proteins (Freibaum et al., 2015; Jovicic et al., 2015; Woerner et al., 2016; Zhang et al., 2015), but also in in aging neurons (Mertens et al., 2015). 

    In this manuscript, the authors describe how expression of poly(GA) repeat-containing proteins leads to the mislocalization and aggregation of RAD23. The appearance of large protein aggregates in the “wrong” cellular compartment is a phenomenon that is also observed in other neurodegenerative diseases. Interestingly, overexpression of RAD23 is sufficient to prevent poly(GA)-induced toxicity in this system, most likely by restoring original RAD23 levels in the nucleus.

    It is important to note that impairment of nucleocytoplasmic transport by protein aggregates is not sufficient to explain all the effects of toxicity observed in c9FTD/ALS (or in other neurodegenerative diseases), however, I believe that a better understanding of the factors that maintain the nucleocytoplasmic compartmentalization is necessary to understand many of these diseases, and that transport across the nuclear envelope is a process that warrants further research.

    For me, an important open question in this regard concerns the order of events: Can defects in nucleocytoplasmic transport be causative for neurodegeneration, or is the collapse of nucleocytoplasmic compartmentalization an event that happens downstream of another insult?

    References:

    Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC, Petrucelli L, Kim HJ, Gao FB, Taylor JP. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):129-33. Epub 2015 Aug 26 PubMed.

    Jovičić A, Mertens J, Boeynaems S, Bogaert E, Chai N, Yamada SB, Paul JW 3rd, Sun S, Herdy JR, Bieri G, Kramer NJ, Gage FH, Van Den Bosch L, Robberecht W, Gitler AD. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci. 2015 Sep;18(9):1226-9. PubMed.

    Woerner AC, Frottin F, Hornburg D, Feng LR, Meissner F, Patra M, Tatzelt J, Mann M, Winklhofer KF, Hartl FU, Hipp MS. Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA. Science. 2016 Jan 8;351(6269):173-6. Epub 2015 Dec 3 PubMed.

    Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):56-61. Epub 2015 Aug 26 PubMed.

    Mertens J, Paquola AC, Ku M, Hatch E, Böhnke L, Ladjevardi S, McGrath S, Campbell B, Lee H, Herdy JR, Gonçalves JT, Toda T, Kim Y, Winkler J, Yao J, Hetzer MW, Gage FH. Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects. Cell Stem Cell. 2015 Oct 6; PubMed.

    View all comments by Mark Hipp

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