Hock EM, Maniecka Z, Hruska-Plochan M, Reber S, Laferrière F, Sahadevan M K S, Ederle H, Gittings L, Pelkmans L, Dupuis L, Lashley T, Ruepp MD, Dormann D, Polymenidou M. Hypertonic Stress Causes Cytoplasmic Translocation of Neuronal, but Not Astrocytic, FUS due to Impaired Transportin Function. Cell Rep. 2018 Jul 24;24(4):987-1000.e7. PubMed.
Recommends
Please login to recommend the paper.
Comments
It is really exciting to observe that the relocalization of FUS is independent of stress granule formation. This suggests a very unique role for TNPO transportins as well, since their relocalization to the cytoplasm is also independent of stress granule localization. I was also very surprised to see that FUS in astrocytes was resistant to cytoplasmic relocalization.
I believe that it is possible osmotic stress plays a role in initiating FUS aggregation leading to human disease, but it’s also possible that aggregation of FUS in disease may be more influenced by genetic factors or through unknown stress mechanisms. In either case, osmotic stress looks like a valuable tool to understand the progression of FUS aggregation in human disease.
View all comments by Brian FreibaumThis manuscript touches on a central theme in ALS, FTD, and related neurodegenerative disorders—the redistribution of RNA binding proteins in association with neurodegeneration. The trigger for cytoplasmic accumulation of these proteins, including TDP43 and FUS, remains unknown. Here, the authors show that hyperosmolar stress leads to mislocalization of FUS but not TDP43, and this seems to depend on redistribution of transportins to the cytoplasm. In opposition to a recent study (Zhang et al., 2018) suggesting that key nucleocytoplasmic transport factors are sequestered by stress granules, Hock et al. demonstrate that FUS mislocalization with hyperosmolar stress is independent of stress granules themselves. Even more interesting is the fact that this type of FUS mislocalization is unique to hyperosmolar stress, and is not witnessed with other forms of cellular stress—this is not a conserved pathway, but rather specific. Moreover, the phenomenon is absent in astrocytes, although readily apparent in neurons and in microglia.
The potential contribution of this mechanism to ALS/FTD pathogenesis is unclear, however. While the authors were unable to detect FUS cytoplasmic inclusions in astrocytes, that does not mean that astrocytes do not play an essential role in the onset and/or progression of disease. Several lines of evidence indicate that astrocytes actively contribute to neurodegeneration in ALS, and perhaps also in FTD (see, for example Song et al., 2016; and Re et al., 2014). Additionally, while the two-hit hypothesis for FUS or TDP43 mislocalization is appealing, it remains to be seen if hyperosmolar stress in particular could be one such “hit.” The authors propose that hyperosmolar therapy during acute treatment for traumatic brain injury may be at least partially responsible for long-term changes in the risk of dementia. One could imagine testing this hypothesis by identifying and following those who received hyperosmolar therapy versus those who did not.
References:
Zhang K, Daigle JG, Cunningham KM, Coyne AN, Ruan K, Grima JC, Bowen KE, Wadhwa H, Yang P, Rigo F, Taylor JP, Gitler AD, Rothstein JD, Lloyd TE. Stress Granule Assembly Disrupts Nucleocytoplasmic Transport. Cell. 2018 May 3;173(4):958-971.e17. Epub 2018 Apr 5 PubMed.
Song S, Miranda CJ, Braun L, Meyer K, Frakes AE, Ferraiuolo L, Likhite S, Bevan AK, Foust KD, McConnell MJ, Walker CM, Kaspar BK. Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis. Nat Med. 2016 Apr;22(4):397-403. Epub 2016 Feb 29 PubMed.
Re DB, Le Verche V, Yu C, Amoroso MW, Politi KA, Phani S, Ikiz B, Hoffmann L, Koolen M, Nagata T, Papadimitriou D, Nagy P, Mitsumoto H, Kariya S, Wichterle H, Henderson CE, Przedborski S. Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron. 2014 Mar 5;81(5):1001-8. Epub 2014 Feb 6 PubMed.
View all comments by Sami BarmadaMayo Clinic
This is a very interesting and thought-provoking paper that sheds light on potential disease mechanisms for frontotemporal dementia (FTD) with FUS protein pathology. It demonstrates that osmotic stress-induced cytoplasmic localization of Transportin 1/2 nuclear import receptors causes mislocalization of FUS and other proteins that depend on transportins for nuclear translocation. While Transportin 1 has recently been identified as a novel stress granule (SG) protein (Markmiller et al., 2018) and SG assembly may disrupt nucleocytoplasmic transport (Zhang et al., 2018), this cytoplasmic accumulation of FUS and transportins appears to be independent of their recruitment into cytoplasmic SGs. This is especially intriguing in the light of related findings recently published back-to-back in Cell, that demonstrate an additional role for Transportin 1 as a chaperone that prevents pathological aggregation of FUS (Guo et al., 2018; Hofweber et al., 2018; Qamar et al., 2018; Yoshizawa et al., 2018). Since hyperosmolarity causes cell shrinkage and macromolecular crowding, these new findings suggest that cytoplasmic recruitment of transportins may act as a protective mechanism to counteract increased levels of protein aggregation, but also cause further cytoplasmic redistribution of aggregation-prone nuclear RNA-binding proteins.
While hypertonic stress in vitro mimics some of the patterns of pathology seen in FTD, additional factors are likely required to cause disease-specific aggregate formation observed in these patients. It will be interesting to see whether findings from this study can be translated into animal models of FTD, e.g., via intracranial sorbitol infusions.
References:
Markmiller S, Soltanieh S, Server KL, Mak R, Jin W, Fang MY, Luo EC, Krach F, Yang D, Sen A, Fulzele A, Wozniak JM, Gonzalez DJ, Kankel MW, Gao FB, Bennett EJ, Lécuyer E, Yeo GW. Context-Dependent and Disease-Specific Diversity in Protein Interactions within Stress Granules. Cell. 2018 Jan 25;172(3):590-604.e13. PubMed.
Zhang K, Daigle JG, Cunningham KM, Coyne AN, Ruan K, Grima JC, Bowen KE, Wadhwa H, Yang P, Rigo F, Taylor JP, Gitler AD, Rothstein JD, Lloyd TE. Stress Granule Assembly Disrupts Nucleocytoplasmic Transport. Cell. 2018 May 3;173(4):958-971.e17. Epub 2018 Apr 5 PubMed.
Guo L, Kim HJ, Wang H, Monaghan J, Freyermuth F, Sung JC, O'Donovan K, Fare CM, Diaz Z, Singh N, Zhang ZC, Coughlin M, Sweeny EA, DeSantis ME, Jackrel ME, Rodell CB, Burdick JA, King OD, Gitler AD, Lagier-Tourenne C, Pandey UB, Chook YM, Taylor JP, Shorter J. Nuclear-Import Receptors Reverse Aberrant Phase Transitions of RNA-Binding Proteins with Prion-like Domains. Cell. 2018 Apr 19;173(3):677-692.e20. PubMed.
Hofweber M, Hutten S, Bourgeois B, Spreitzer E, Niedner-Boblenz A, Schifferer M, Ruepp MD, Simons M, Niessing D, Madl T, Dormann D. Phase Separation of FUS Is Suppressed by Its Nuclear Import Receptor and Arginine Methylation. Cell. 2018 Apr 19;173(3):706-719.e13. PubMed.
Qamar S, Wang G, Randle SJ, Ruggeri FS, Varela JA, Lin JQ, Phillips EC, Miyashita A, Williams D, Ströhl F, Meadows W, Ferry R, Dardov VJ, Tartaglia GG, Farrer LA, Kaminski Schierle GS, Kaminski CF, Holt CE, Fraser PE, Schmitt-Ulms G, Klenerman D, Knowles T, Vendruscolo M, St George-Hyslop P. FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions. Cell. 2018 Apr 19;173(3):720-734.e15. PubMed.
Yoshizawa T, Ali R, Jiou J, Fung HY, Burke KA, Kim SJ, Lin Y, Peeples WB, Saltzberg D, Soniat M, Baumhardt JM, Oldenbourg R, Sali A, Fawzi NL, Rosen MK, Chook YM. Nuclear Import Receptor Inhibits Phase Separation of FUS through Binding to Multiple Sites. Cell. 2018 Apr 19;173(3):693-705.e22. PubMed.
View all comments by Wilfried RossollMake a Comment
To make a comment you must login or register.