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FUS as disease protein in amyotrophic lateral sclerosis and frontotemporal dementia: Transgenic mouse models and pathomechanisms

English title FUS as disease protein in amyotrophic lateral sclerosis and frontotemporal dementia: Transgenic mouse models and pathomechanisms
Applicant Neumann Manuela
Number 132864
Funding scheme Project funding (Div. I-III)
Research institution Neuropathologie Universität Tübingen
Institution of higher education University of Zurich - ZH
Main discipline Neurophysiology and Brain Research
Start/End 01.10.2010 - 30.09.2013
Approved amount 331'000.00
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Keywords (7)

Neurodegeneration; FUS/TLS; Amyotrophic lateral sclerosis; fused in sarcoma; transgenic mouse; RNA processing; stress granules

Lay Summary (English)

Lead
Lay summary
Amyotrophic lateral sclerosis (ALS) is the most common neuromuscular disease and frontotemporal dementia (FTD) is the second most common cause of dementia in patients under the age of 65. Recently, mutations in the gene encoding for the DNA/RNA binding protein fused in sarcoma (FUS) have been identified as cause of the disease in a subset of familial ALS cases and subsequent work from our group have identified FUS also as disease protein in a subset of FTD patients, thereby providing strong evidence that both conditions share common pathomechanisms and can be subsumed under the term FUS-opathies. The characteristic hallmark lesion in patients with FUS-opathies is the presence of abnormal protein clumps in the cell bodies of neurons and glial cells composed of the protein FUS. The pathomechanisms underlying FUS-opathies and FUS-mediated neurodegeneration are currently not understood. However, the described roles of FUS in RNA transcription, splicing and trafficking, and its striking functional and structural similarity with TDP-43, another DNA/RNA binding protein involved in ALS and FTD, imply alterations in RNA processing of specific targets as key event in the pathogenesis of ALS and FTD. The working hypothesis of our proposal is that altered nuclear import of FUS, either by pathogenic FUS mutations and/or by posttranslational modifications of FUS is a key event which then leads to accumulation of cytoplasmic FUS. Cytoplasmic FUS accumulation then mediates cell death either by a direct toxic effect or by sequestration and consequent depletion of other vital factors into the FUS-inclusions such as other RNA binding proteins and/or specific mRNA transcripts.In order to test this hypothesis we attempt to (1) establish a novel transgenic mouse model by expressing a human pathogenic truncated form of FUS lacking its entire nuclear localization signal and to determine its impact on morphological, biochemical and behavioral levels; (2) identify posttranslational modifications of FUS modulating its nuclear import; and (3) apply proteomics and RIP-ChIP technology to characterize co-sequestered proteins and mRNAs in FUS inclusions and to analyze their effect in FUS-mediated cell death. It is expected that the results obtained in this proposal will provide important new insights into the mechanistic basis underlying ALS and FTD and identified specific disease-relevant posttranslational modifications and co-sequestered mRNA transcripts/proteins may become promising targets for new therapeutic approaches.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Frontotemporal lobar degeneration and amyotrophic lateral sclerosis: Molecular similarities and differences
Neumann M. (2013), Frontotemporal lobar degeneration and amyotrophic lateral sclerosis: Molecular similarities and differences, in Revue Neurologique, 169(10), 793-798.
Mutations in protein N-arginine methyltransferases are not the cause of FTLD-FUS
Ravenscroft, Baker Matt C., Rutherford Nicola J., Neumann Manuela, MacKenzie Ian R A, Josephs Keith A., Boeve Bradley F., Petersen Ronald C., Halliday Glenda Margaret, Kril Jillian J., Van Swieten John Cornelis, Seeley William W., Dickson Dennis W., Rademakers Rosa (2013), Mutations in protein N-arginine methyltransferases are not the cause of FTLD-FUS, in Neurobiology of Aging, 34(9), 2235.e11-e13.
The multifaceted role of glial cells in amyotrophic lateral sclerosis.
Valori Chiara F, Brambilla Liliana, Martorana Francesca, Rossi Daniela (2013), The multifaceted role of glial cells in amyotrophic lateral sclerosis., in Cellular and molecular life sciences : CMLS, 1.
Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations: A clinico-genetic study in Germany
Waibel Stefan, Neumann Manuela, Rosenbohm Angela, Birve Anna, Volk Alexander E., Weishaupt Jochen H., Meyer Thomas, Müller Ulrich, Andersen P. M., Ludolph Albert Christian (2013), Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations: A clinico-genetic study in Germany, in European Journal of Neurology, 20(3), 540-546.
Advances in understanding the molecular basis of frontotemporal dementia.
Rademakers Rosa, Neumann Manuela, Mackenzie Ian R (2012), Advances in understanding the molecular basis of frontotemporal dementia., in Nature reviews. Neurology, x-x.
Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS
Dormann Dorothee, Madl Tobias, Valori Chiara F., Bentmann Eva, Tahirovic Sabina, Abou-Ajram Claudia, Kremmer Elisabeth, Ansorge Olaf, Mackenzie Ian Ra A, Neumann Manuela, Haass Christian (2012), Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS, in EMBO Journal, 31(22), 4258-4275.
FET proteins in frontotemporal dementia and amyotrophic lateral sclerosis.
Mackenzie Ian R A, Neumann Manuela (2012), FET proteins in frontotemporal dementia and amyotrophic lateral sclerosis., in Brain research, 1462, 40-3.
Mechanisms of disease in frontotemporal lobar degeneration: Gain of function versus loss of function effects
Halliday Glenda Margaret, Bigio Eileen H., Cairns Nigel J., Neumann Manuela, Mackenzie Ian Ra A, Mann David (2012), Mechanisms of disease in frontotemporal lobar degeneration: Gain of function versus loss of function effects, in Acta Neuropathologica, 124(3), 373-382.
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.
Neumann Manuela, Valori Chiara F, Ansorge Olaf, Kretzschmar Hans A, Munoz David G, Kusaka Hirofumi, Yokota Osamu, Ishihara Kenji, Ang Lee-Cyn, Bilbao Juan M, Mackenzie Ian R A (2012), 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., in Acta Neuropathologica, x-x.
FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations.
Neumann Manuela, Bentmann Eva, Dormann Dorothee, Jawaid Ali, Dejesus-Hernandez Mariely, Ansorge Olaf, Roeber Sigrun, Kretzschmar Hans A, Munoz David G, Kusaka Hirofumi, Yokota Osamu, Ang Lee-Cyn, Bilbao Juan, Rademakers Rosa, Haass Christian, Mackenzie Ian R A (2011), FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations., in Brain : a journal of neurology, 134(Pt 9), 2595-609.
Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation.
Mackenzie Ian R A, Ansorge Olaf, Strong Michael, Bilbao Juan, Zinman Lorne, Ang Lee-Cyn, Baker Matt, Stewart Heather, Eisen Andrew, Rademakers Rosa, Neumann Manuela (2011), Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation., in Acta neuropathologica, 122(1), 87-98.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
23rd international symposium on ALS/MND Talk given at a conference 05.12.2012 Chicago, United States of America Valori Chiara;
8th International Conference on Frontotemporal Dementias, Manchester, UK Talk given at a conference 05.09.2012 Manchester, Great Britain and Northern Ireland Neumann Manuela;
56th annual meeting of the German Society for Neuropathology and Neuroanatomy Talk given at a conference 21.09.2011 Tübingen, Germany Valori Chiara;


Abstract

Amyotrophic lateral sclerosis (ALS) is the most common neuromuscular disease and frontotemporal dementia (FTD) is the second most common cause of dementia in patients under the age of 65. Currently there is no cure for these devastating diseases. Recently, mutations in the gene encoding for the DNA/RNA binding protein fused in sarcoma (FUS) have been identified as cause in a subset of familial ALS and subsequently recent work from our group have identified FUS also as disease protein in ~10 % of sporadic FTD patients, thereby providing strong evidence that both conditions share a common pathomechanism. The characteristic hallmark lesion in FUS-opathies is the presence of FUS-positive cytoplasmic inclusions in neurons and oligodendrocytes, however, the pathogenesis of FUS-opathies is not understood. The focus of this proposal is to unravel the mechanisms leading to cytoplasmic FUS accumulation and to understand the mechanisms underlying FUS-mediated neurodegeneration. We postulate that altered nuclear import of FUS, either by pathogenic FUS mutations and/or by posttranslational modifications of FUS (specifically in the case of sporadic FUS-opathies) is a key event which then leads to accumulation of cytoplasmic FUS, which then mediates cell death either by a direct toxic effect or by sequestration and consequent depletion of other vital factors into the FUS-inclusions such as other RNA binding proteins and/or specific mRNA transcripts. Currently, there is no in-vivo model available mimicking human FUS-opathies and it is obvious that a valid mouse model mimicking human FUS-pathology is crucial for our further understanding of FUS-related pathogenesis. Therefore one major focus (AIM1) of this project is to generate and investigate a transgenic mouse model by overexpressing our newly identified first truncating mutation of FUS (R495X) resulting in deletion of the complete predicted nuclear-localization signal of FUS. Transgenic mice will be analyzed by histological and biochemical techniques in comparison to human FUS-opathies and will allow us to address whether impaired nuclear import of FUS alone is sufficient to recapitulate human FUS pathology and cell death. In AIM2 we want to determine the role of posttranslational modifications, specifically phosphorylation and arginine methylation, of FUS on subcellular distribution and inclusion body formation which will be crucial for our further understanding of sporadic FUS-opathies. In order to elucidate the consequences of FUS accumulation and FUS-mediated cell death we attempt to characterize the composition of FUS inclusions in AIM3 with respect to other co-sequestered protein components and mRNA transcripts by proteomics and RIP-ChIP approaches. These experiments will deliver further insights into FUS-mediated neurodegeneration and the identification of specific disease-relevant posttranslational modifications and co-sequestered mRNA transcripts/proteins may become promising targets for new therapeutic approaches.
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