Dormann D, Madl T, Valori CF, Bentmann E, Tahirovic S, Abou-Ajram C, Kremmer E, Ansorge O, Mackenzie IR, Neumann M, Haass C.
Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS.
EMBO J. 2012 Sep 11;
PubMed.
This is a key paper by the Haass lab, raising several important issues regarding our understanding of pathological mechanisms mediated by the FUS nuclear factor in ALS and FTLD (termed ALS-FUS and FTLD-FUS, respectively). Rather puzzlingly, in fact, was that although ALS-FUS and FTLD-FUS were shown to have overlapping clinical phenotype and neuropathology, there was no explanation for why individuals affected by the same protein pathology developed one form of the disease as opposed to the other. In this work, the convincing demonstration that the FUS protein is methylated in ALS-FUS-related cases but not in FTLD-FUS-related cases has gone a long way in helping to address this long-standing question. Indeed, together with recent findings that the FUS protein co-aggregates with two FET family proteins and the transportin receptor itself in FTLD-FUS cases, but not in ALS-FUS, the study by Dorothee Dormann, Christian Haass, and colleagues provides additional evidence that these two diseases may actually be initiated by distinct pathomechanisms. Most importantly, they implicate alterations in arginine methylation in pathogenesis, an observation that will have profound influence on future research in this field.
It can be easily foreseen, in fact, that this work will act as an important springboard for research in an area rather underappreciated until this moment: the post-translational modifications of these risk proteins. In this respect, it should be kept in mind that post-translational modifications are also common for non-FUS versions of these diseases, such as the aberrant phosphorylation and ubiquitination of TDP-43 in ALS and FTLD. Presently, very little is known regarding the effects these modifications have on the biological (nuclear import, export, aggregation, toxicity, etc.) or functional properties (pre-mRNA splicing, mRNA transport, and other RNA processing events) of all these disease proteins. That gap in our knowledge should be addressed as soon as possible, since, as the authors show, it may hold the key for crucial advancements in our understanding of these diseases.
Of course, like all seminal findings of this kind, these observations also spark a number of questions about which we can only speculate at the moment. These range from the very specific, such as whether different methylation patterns may be connected not just with disease but also with other characteristics such as age of onset, to the very general, such as identifying the different molecular pathomechanisms that must be activated in either case. I therefore expect that future research will be very busy in all these directions.
The paper clearly demonstrates that arginine methylation of FUS is an important modulator for nuclear import of FUS and its homologues, TAF15 and EWS, as demonstrated in vitro and in cell culture.
In my opinion, the most exciting finding is the difference we observed in the methylation status of FUS in the inclusions in the spectrum of FUSopathies using the novel methylation-specific antibodies. While FUS was methylated in cases with FUS mutations (that usually present with ALS), it seems to be un- or hypomethylated in FTLD-FUS.
Together with some other recent findings from my group, working together with Ian Mackenzie, on differences between FUSopathies with FUS mutations and those without (Neumann et al., 2011; Neumann et al., 2012), these data fit into the hypothesis we published in a recent review (Rademakers et al., 2012) of distinct pathomechanisms underlying inclusion body formation in FUSopathies by implying alterations of post-translational modifications of FET proteins as the most plausible scenario.
There are still a lot of open questions, since arginine methylation, in general, is not very well understood. Which of the methyltransferases is the main enzyme for arginine methylations of FET proteins in the brain? Are individual sites for arginine methylation more important than others? How reversible is the process?
Given the fact that a lot of RNA binding proteins are arginine methylated, and [considering] the increasing number of RNA binding proteins involved in ALS and FTD, it is possible that dysregulation of arginine methylation might be involved also in non-FUSopathies. However, currently there are no data demonstrating arginine methylation of TDP-43, the other most common FTD/ALS protein.
References:
Neumann M, Bentmann E, Dormann D, Jawaid A, Dejesus-Hernandez M, Ansorge O, Roeber S, Kretzschmar HA, Munoz DG, Kusaka H, Yokota O, Ang LC, Bilbao J, Rademakers R, Haass C, Mackenzie IR.
FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations.
Brain. 2011 Sep;134(Pt 9):2595-609.
PubMed.
Neumann M, Valori CF, Ansorge O, Kretzschmar HA, Munoz DG, Kusaka H, Yokota O, Ishihara K, Ang LC, Bilbao JM, Mackenzie IR.
Transportin 1 accumulates specifically with FET proteins but no other transportin cargos in FTLD-FUS and is absent in FUS inclusions in ALS with FUS mutations.
Acta Neuropathol. 2012 Nov;124(5):705-16.
PubMed.
Rademakers R, Neumann M, Mackenzie IR.
Advances in understanding the molecular basis of frontotemporal dementia.
Nat Rev Neurol. 2012 Jun 26;8(8):423-34.
PubMed.
Comments
International Centre for Genetic Engineering and Biotechnology
This is a key paper by the Haass lab, raising several important issues regarding our understanding of pathological mechanisms mediated by the FUS nuclear factor in ALS and FTLD (termed ALS-FUS and FTLD-FUS, respectively). Rather puzzlingly, in fact, was that although ALS-FUS and FTLD-FUS were shown to have overlapping clinical phenotype and neuropathology, there was no explanation for why individuals affected by the same protein pathology developed one form of the disease as opposed to the other. In this work, the convincing demonstration that the FUS protein is methylated in ALS-FUS-related cases but not in FTLD-FUS-related cases has gone a long way in helping to address this long-standing question. Indeed, together with recent findings that the FUS protein co-aggregates with two FET family proteins and the transportin receptor itself in FTLD-FUS cases, but not in ALS-FUS, the study by Dorothee Dormann, Christian Haass, and colleagues provides additional evidence that these two diseases may actually be initiated by distinct pathomechanisms. Most importantly, they implicate alterations in arginine methylation in pathogenesis, an observation that will have profound influence on future research in this field.
It can be easily foreseen, in fact, that this work will act as an important springboard for research in an area rather underappreciated until this moment: the post-translational modifications of these risk proteins. In this respect, it should be kept in mind that post-translational modifications are also common for non-FUS versions of these diseases, such as the aberrant phosphorylation and ubiquitination of TDP-43 in ALS and FTLD. Presently, very little is known regarding the effects these modifications have on the biological (nuclear import, export, aggregation, toxicity, etc.) or functional properties (pre-mRNA splicing, mRNA transport, and other RNA processing events) of all these disease proteins. That gap in our knowledge should be addressed as soon as possible, since, as the authors show, it may hold the key for crucial advancements in our understanding of these diseases.
Of course, like all seminal findings of this kind, these observations also spark a number of questions about which we can only speculate at the moment. These range from the very specific, such as whether different methylation patterns may be connected not just with disease but also with other characteristics such as age of onset, to the very general, such as identifying the different molecular pathomechanisms that must be activated in either case. I therefore expect that future research will be very busy in all these directions.
View all comments by Emanuele BurattiUniversity of Tübingen and DZNE AG Neumann
The paper clearly demonstrates that arginine methylation of FUS is an important modulator for nuclear import of FUS and its homologues, TAF15 and EWS, as demonstrated in vitro and in cell culture.
In my opinion, the most exciting finding is the difference we observed in the methylation status of FUS in the inclusions in the spectrum of FUSopathies using the novel methylation-specific antibodies. While FUS was methylated in cases with FUS mutations (that usually present with ALS), it seems to be un- or hypomethylated in FTLD-FUS.
Together with some other recent findings from my group, working together with Ian Mackenzie, on differences between FUSopathies with FUS mutations and those without (Neumann et al., 2011; Neumann et al., 2012), these data fit into the hypothesis we published in a recent review (Rademakers et al., 2012) of distinct pathomechanisms underlying inclusion body formation in FUSopathies by implying alterations of post-translational modifications of FET proteins as the most plausible scenario.
There are still a lot of open questions, since arginine methylation, in general, is not very well understood. Which of the methyltransferases is the main enzyme for arginine methylations of FET proteins in the brain? Are individual sites for arginine methylation more important than others? How reversible is the process?
Given the fact that a lot of RNA binding proteins are arginine methylated, and [considering] the increasing number of RNA binding proteins involved in ALS and FTD, it is possible that dysregulation of arginine methylation might be involved also in non-FUSopathies. However, currently there are no data demonstrating arginine methylation of TDP-43, the other most common FTD/ALS protein.
References:
Neumann M, Bentmann E, Dormann D, Jawaid A, Dejesus-Hernandez M, Ansorge O, Roeber S, Kretzschmar HA, Munoz DG, Kusaka H, Yokota O, Ang LC, Bilbao J, Rademakers R, Haass C, Mackenzie IR. FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations. Brain. 2011 Sep;134(Pt 9):2595-609. PubMed.
Neumann M, Valori CF, Ansorge O, Kretzschmar HA, Munoz DG, Kusaka H, Yokota O, Ishihara K, Ang LC, Bilbao JM, Mackenzie IR. Transportin 1 accumulates specifically with FET proteins but no other transportin cargos in FTLD-FUS and is absent in FUS inclusions in ALS with FUS mutations. Acta Neuropathol. 2012 Nov;124(5):705-16. PubMed.
Rademakers R, Neumann M, Mackenzie IR. Advances in understanding the molecular basis of frontotemporal dementia. Nat Rev Neurol. 2012 Jun 26;8(8):423-34. PubMed.
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