ALS ‐ associated fused in sarcoma (FUS) mutations disrupt Transportin ‐ mediated nuclear import by Dorothee Dormann, Ramona Rodde, Dieter Edbauer, Eva.

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ALS ‐ associated fused in sarcoma (FUS) mutations disrupt Transportin ‐ mediated nuclear import by Dorothee Dormann, Ramona Rodde, Dieter Edbauer, Eva Bentmann, Ingeborg Fischer, Alexander Hruscha, Manuel E Than, Ian R A Mackenzie, Anja Capell, Bettina Schmid, Manuela Neumann, and Christian Haass EMBO J. Volume 29(16): August 18, 2010 ©2010 by European Molecular Biology Organization

The C ‐ terminal tail of FUS (FUS514−526) is necessary and sufficient for nuclear import. Dorothee Dormann et al. EMBO J. 2010;29: ©2010 by European Molecular Biology Organization

fALS ‐ associated mutations in important residues of the FUS NLS disrupt nuclear import. Dorothee Dormann et al. EMBO J. 2010;29: ©2010 by European Molecular Biology Organization

The FUS ‐ P525L mutation disrupts nuclear import in primary neurons and prevents import of a cytosolic reporter in vitro and in vivo. Dorothee Dormann et al. EMBO J. 2010;29: ©2010 by European Molecular Biology Organization

Transportin is required for nuclear import of FUS. (A) The two Trp homologues, Trp1 and Trp2, were silenced by siRNA ‐ mediated knockdown, using two different siRNA pools (no. 1 and no. 2). Dorothee Dormann et al. EMBO J. 2010;29: ©2010 by European Molecular Biology Organization

Expression of a Trp ‐ specific peptide inhibitor leads to the cytosolic redistribution of FUS, but not TDP ‐ 43. Dorothee Dormann et al. EMBO J. 2010;29: ©2010 by European Molecular Biology Organization

Redistribution of FUS into cytoplasmic stress granules. Dorothee Dormann et al. EMBO J. 2010;29: ©2010 by European Molecular Biology Organization

Neuronal cytoplasmic inclusions (NCIs) in patients with FUS pathology contain the stress granule marker proteins PABP ‐ 1 and eIF4G. Dorothee Dormann et al. EMBO J. 2010;29: ©2010 by European Molecular Biology Organization

C ‐ terminal fALS ‐ associated FUS mutations favour recruitment of FUS into stress granules. Dorothee Dormann et al. EMBO J. 2010;29: ©2010 by European Molecular Biology Organization

A two hit model of FUS pathology. Dorothee Dormann et al. EMBO J. 2010;29: ©2010 by European Molecular Biology Organization