title: Cell-to-Cell Transmission of Dipeptide Repeat Proteins Linked to C9orf72-ALS/FTD.
abstract: Aberrant hexanucleotide repeat expansions in C9orf72 are the most common genetic change underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). RNA transcripts containing these expansions undergo repeat-associated non-ATG translation (RAN-T) to form five dipeptide repeat proteins (DPRs). DPRs are found as aggregates throughout the CNS of C9orf72-ALS/FTD patients, and some cause degeneration when expressed in vitro in neuronal cultures and in vivo in animal models. The spread of characteristic disease-related proteins drives the progression of pathology in many neurodegenerative diseases. While DPR toxic mechanisms continue to be investigated, the potential for DPRs to spread has yet to be determined. Using different experimental cell culture platforms, including spinal motor neurons derived from induced pluripotent stem cells from C9orf72-ALS patients, we found evidence for cell-to-cell spreading of DPRs via exosome-dependent and exosome-independent pathways, which may be relevant to disease.
authors.affiliation: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Westergard
authors.affiliation: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.
authors.forename: Brigid K
authors.initials: BK
authors.lastname: Jensen
authors.affiliation: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.
authors.forename: Xinmei
authors.initials: X
authors.lastname: Wen
authors.affiliation: Stem Cell Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.
authors.forename: Jingli
authors.initials: J
authors.lastname: Cai
authors.affiliation: Stem Cell Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kropf
authors.affiliation: Stem Cell Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Iacovitti
authors.affiliation: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.
authors.forename: Piera
authors.initials: P
authors.lastname: Pasinelli
authors.affiliation: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA. Electronic address: davide.trotti@jefferson.edu.
authors.forename: Davide
authors.initials: D
authors.lastname: Trotti
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D000073885:C9orf72 Protein / Q000378:metabolism*; D004151:Dipeptides / Q000737:chemistry* / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D051381:Rats; D020449:Repetitive Sequences, Amino Acid; D013116:Spinal Cord / Q000473:pathology
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004151:Dipeptides
keywords: ALS; C9orf72; DPR; FTD; cell-to-cell transmission; dipeptide repeat proteins; exosomes; propagation