Cell-to-Cell Transmission of Dipeptide Repeat Proteins Linked to C9orf72-ALS/FTD

Thomas Westergard; Brigid K. Jensen; Xinmei Wen; Jingli Cai; Elizabeth Kropf; Lorraine Iacovitti; Piera Pasinelli; Davide Trotti

doi:10.1016/j.celrep.2016.09.032

Cell Reports (Oct 2016)

Cell-to-Cell Transmission of Dipeptide Repeat Proteins Linked to C9orf72-ALS/FTD

Thomas Westergard,
Brigid K. Jensen,
Xinmei Wen,
Jingli Cai,
Elizabeth Kropf,
Lorraine Iacovitti,
Piera Pasinelli,
Davide Trotti

Affiliations

Thomas Westergard: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA
Brigid K. Jensen: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA
Xinmei Wen: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA
Jingli Cai: Stem Cell Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA
Elizabeth Kropf: Stem Cell Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA
Lorraine Iacovitti: Stem Cell Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA
Piera Pasinelli: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA
Davide Trotti: Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA

DOI: https://doi.org/10.1016/j.celrep.2016.09.032
Journal volume & issue: Vol. 17, no. 3
pp. 645 – 652

Abstract

Read online

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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

About the journal

Abstract

Keywords