title: Requirements for stress granule recruitment of fused in sarcoma (FUS) and TAR DNA-binding protein of 43 kDa (TDP-43).
abstract: Cytoplasmic inclusions containing TAR DNA-binding protein of 43 kDa (TDP-43) or Fused in sarcoma (FUS) are a hallmark of amyotrophic lateral sclerosis (ALS) and several subtypes of frontotemporal lobar degeneration (FTLD). FUS-positive inclusions in FTLD and ALS patients are consistently co-labeled with stress granule (SG) marker proteins. Whether TDP-43 inclusions contain SG markers is currently still debated. We determined the requirements for SG recruitment of FUS and TDP-43 and found that cytoplasmic mislocalization is a common prerequisite for SG recruitment of FUS and TDP-43. For FUS, the arginine-glycine-glycine zinc finger domain, which is the protein's main RNA binding domain, is most important for SG recruitment, whereas the glycine-rich domain and RNA recognition motif (RRM) domain have a minor contribution and the glutamine-rich domain is dispensable. For TDP-43, both the RRM1 and the C-terminal glycine-rich domain are required for SG localization. ALS-associated point mutations located in the glycine-rich domain of TDP-43 do not affect SG recruitment. Interestingly, a 25-kDa C-terminal fragment of TDP-43, which is enriched in FTLD/ALS cortical inclusions but not spinal cord inclusions, fails to be recruited into SG. Consistently, inclusions in the cortex of FTLD patients, which are enriched for C-terminal fragments, are not co-labeled with the SG marker poly(A)-binding protein 1 (PABP-1), whereas inclusions in spinal cord, which contain full-length TDP-43, are frequently positive for this marker protein.
authors.affiliation: Adolf-Butenandt-Institute, Biochemistry, Ludwig-Maximilians-University, München, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Bentmann
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.forename: Sabina
authors.initials: S
authors.lastname: Tahirovic
authors.forename: Ramona
authors.initials: R
authors.lastname: Rodde
authors.forename: Dorothee
authors.initials: D
authors.lastname: Dormann
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D001665:Binding Sites / Q000502:physiology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism* / Q000473:pathology; D005973:Glutamine / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D006367:HeLa Cells; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000502:physiology; D039122:Poly(A)-Binding Protein I / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013312:Stress, Physiological / Q000502:physiology; D016335:Zinc Fingers / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D039122:Poly(A)-Binding Protein I; D034702:RNA-Binding Protein FUS; D005973:Glutamine; D012313:RNA; D005998:Glycine