The FUS about arginine methylation in ALS and FTLD

Abstract

EMBO J (2012) 31 22, 4258–4275 doi:; DOI: 10.1038/emboj.2012.261; published online September 11 2012

In a time where links between amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) neurodegeneration are becoming increasingly clear, it is important to establish the convergent and divergent mechanisms responsible for this. Accordingly, Dormann et al (2012) have identified that methylation of the Fused in sarcoma (FUS) RGG3 domain is involved in the cytoplasmic mislocalisation of ALS-FUS mutants, through a transportin-dependent mechanism. By contrast, hypomethylation in this domain may play a role in the aberrant accumulation of FUS in FTLD-FUS. This work showcases arginine methylation as a phenomenon to watch out for in neurodegenerative pathology.

Figure 1

(A) Schematic diagram showing the domain structure of FUS. SYGQ-rich, serine, tyrosine, glycine, glutamine-rich domain; RRM, RNA recognition motif; ZnF, zinc finger; PY, proline-tyrosine nuclear localization signal (PY-NLS). (B) Schematic diagram summarizing the divergent mechanisms by which arginine methylation (or absence thereof) may bring about FUS mislocalization and accumulation in ALS-FUS and FTLD-FUS. In ALS-FUS caused by FUS mutations, neuronal cytoplasmic inclusions contain methylated FUS, but are negative for EWS, TAF15 and TRN. Dormann et al (2012) propose that these FUS-specific inclusions result from the combination of a genetic defect (point mutations in the PY-NLS that impair transportin binding) and post-translational modification (arginine methylation in RGG3 domain that also impairs transportin binding). By contrast in FTLD-FUS, neuronal cytoplasmic inclusions contain all three FET proteins and transportin, but are not immunoreactive with meFUS-specific antibodies. It is therefore possible that hypomethylation of the FET proteins and thus increased transportin binding may be involved in the co-deposition of these proteins in FTLD-FUS.