Neurodegeneration; FUS/TLS; Amyotrophic lateral sclerosis; fused in sarcoma; transgenic mouse; RNA processing; stress granules
Neumann M. (2013), Frontotemporal lobar degeneration and amyotrophic lateral sclerosis: Molecular similarities and differences, in Revue Neurologique
, 169(10), 793-798.
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.
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
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.
Rademakers Rosa, Neumann Manuela, Mackenzie Ian R (2012), Advances in understanding the molecular basis of frontotemporal dementia., in Nature reviews. Neurology
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.
Mackenzie Ian R A, Neumann Manuela (2012), FET proteins in frontotemporal dementia and amyotrophic lateral sclerosis., in Brain research
, 1462, 40-3.
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.
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
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.
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.
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.