The Role of Post-Translational Modifications on Prion-Like Aggregation and Liquid-Phase Separation of FUS - PubMed (original) (raw)

Review

The Role of Post-Translational Modifications on Prion-Like Aggregation and Liquid-Phase Separation of FUS

Shannon N Rhoads et al. Int J Mol Sci. 2018.

Abstract

Subcellular mislocalization and aggregation of the human FUS protein occurs in neurons of patients with subtypes of amyotrophic lateral sclerosis and frontotemporal dementia. FUS is one of several RNA-binding proteins that can functionally self-associate into distinct liquid-phase droplet structures. It is postulated that aberrant interactions within the dense phase-separated state can potentiate FUS's transition into solid prion-like aggregates that cause disease. FUS is post-translationally modified at numerous positions, which affect both its localization and aggregation propensity. These modifications may influence FUS-linked pathology and serve as therapeutic targets.

Keywords: ALS; FTLD; FUS; LLPS; amyloid; prion.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. The funding sponsors had no role in the writing of the manuscript.

Figures

Figure 1

Schematic of human FUS domain organization. Approximately the first half of FUS has little sequence complexity and consists mostly of a few different amino acids. This region is sometimes called the low-complexity domain. The prion-like domain (PrLD) shares sequence composition with domains in yeast proteins that form self-replicating amyloid structures (i.e., prions). FUS’s PrLD is highly phosphorylated following certain stresses. The RGG domains contain the triplet repeat motif of arginine–glycine–glycine, which are extensively methylated. FUS also contains an RNA-recognition motif (RRM), a zinc-finger domain (ZnF), and a proline–tyrosine nuclear localization signal (PY–NLS). The red stars indicate ALS mutation sites that are also post-translationally modified (see Table 1).

References

1. Pérez-Losada J., Pintado B., Gutiérrez-Adán A., Flores T., Bañares-González B., Del Campo J.C., Martín-Martín J.F., Battaner E., Sánchez-García I. The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice. Oncogene. 2000;19:2413–2422. doi: 10.1038/sj.onc.1203572. - DOI - PubMed
1. Kwiatkowski T.J., Jr., Bosco D.A., Leclerc A.L., Tamrazian E., Vanderburg C.R., Russ C., Davis A., Gilchrist J., Kasarskis E.J., Munsat T., et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009;323:1205–1208. doi: 10.1126/science.1166066. - DOI - PubMed
1. Vance C., Rogelj B., Hortobagyi T., De Vos K.J., Nishimura A.L., Sreedharan J., Hu X., Smith B., Ruddy D., Wright P., et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323:1208–1211. doi: 10.1126/science.1165942. - DOI - PMC - PubMed
1. Neumann M., Rademakers R., Roeber S., Baker M., Kretzschmar H.A., Mackenzie I.R. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain. 2009;132:2922–2931. doi: 10.1093/brain/awp214. - DOI - PMC - PubMed
1. Sharma A., Lyashchenko A.K., Lu L., Nasrabady S.E., Elmaleh M., Mendelsohn M., Nemes A., Tapia J.C., Mentis G.Z., Shneider N.A. ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function. Nat. Commun. 2016;7:10465. doi: 10.1038/ncomms10465. - DOI - PMC - PubMed

The Role of Post-Translational Modifications on Prion-Like Aggregation and Liquid-Phase Separation of FUS - PubMed (original) (raw)