title: The prion-like RNA-processing protein HNRPDL forms inherently toxic amyloid-like inclusion bodies in bacteria.
abstract: BACKGROUND
  The formation of protein inclusions is connected to the onset of many human diseases. Human RNA binding proteins containing intrinsically disordered regions with an amino acid composition resembling those of yeast prion domains, like TDP-43 or FUS, are being found to aggregate in different neurodegenerative disorders. The structure of the intracellular inclusions formed by these proteins is still unclear and whether these deposits have an amyloid nature or not is a matter of debate. Recently, the aggregation of TDP-43 has been modelled in bacteria, showing that TDP-43 inclusion bodies (IBs) are amorphous but intrinsically neurotoxic. This observation raises the question of whether it is indeed the lack of an ordered structure in these human prion-like protein aggregates the underlying cause of their toxicity in different pathological states.
  
  
  RESULTS
  Here we characterize the IBs formed by the human prion-like RNA-processing protein HNRPDL. HNRPDL is linked to the development of limb-girdle muscular dystrophy 1G and shares domain architecture with TDP-43. We show that HNRPDL IBs display characteristic amyloid hallmarks, since these aggregates bind to amyloid dyes in vitro and inside the cell, they are enriched in intermolecular β-sheet conformation and contain inner amyloid-like fibrillar structure. In addition, despite their ordered structure, HNRPDL IBs are highly neurotoxic.
  
  
  CONCLUSIONS
  Our results suggest that at least some of the disorders caused by the aggregation of human prion-like proteins would rely on the formation of classical amyloid assemblies rather than being caused by amorphous aggregates. They also illustrate the power of microbial cell factories to model amyloid aggregation.
authors.affiliation: Institut de Biotecnologia i Biomedicina, Departament de Bioquimica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Spain. Susanna.Navarro.Cantero@uab.cat.
authors.forename: Susanna
authors.initials: S
authors.lastname: Navarro
authors.affiliation: Institut de Biotecnologia i Biomedicina, Departament de Bioquimica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Spain. Patrizia.Marinelli@uab.cat.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Marinelli
authors.affiliation: Institut de Biotecnologia i Biomedicina, Departament de Bioquimica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Spain. marta.diaz11@gmail.com.
authors.forename: Marta
authors.initials: M
authors.lastname: Diaz-Caballero
authors.affiliation: Institut de Biotecnologia i Biomedicina, Departament de Bioquimica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Spain. salvador.ventura@uab.es.
authors.forename: Salvador
authors.initials: S
authors.lastname: Ventura
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D001419:Bacteria / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D011328:Prions / Q000235:genetics*; D012313:RNA / Q000378:metabolism*
chemical_list: D000682:Amyloid; D011328:Prions; D012313:RNA