Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms
Leslie I Grad, Justin J Yerbury, Bradley J Turner, William C Guest, Edward Pokrishevsky, Megan A O'Neill, Anat Yanai, Judith M Silverman, Rafaa Zeineddine, Lisa Corcoran, Janet R Kumita, Leila M Luheshi, Masoud Yousefi, Bradley M Coleman, Andrew F Hill, Steven S Plotkin, Ian R Mackenzie, Neil R Cashman
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | NATL ACAD SCIENCES | Published : 2014
Amyotrophic lateral sclerosis (ALS) is predominantly sporadic, but associated with heritable genetic mutations in 5-10% of cases, including those in Cu/Zn superoxide dismutase (SOD1). We previously showed that misfolding of SOD1 can be transmitted to endogenous human wild-type SOD1 (HuWtSOD1) in an intracellular compartment. Using NSC-34 motor neuron-like cells, we now demonstrate that misfolded mutant and HuWtSOD1 can traverse between cells via two nonexclusive mechanisms: protein aggregates released from dying cells and taken up by macropinocytosis, and exosomes secreted from living cells. Furthermore, once HuWtSOD1 propagation has been established, misfolding of HuWtSOD1 can be efficientl..View full abstract
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Awarded by National Health and Medical Research Council (NHMRC)
Awarded by NHMRC
We thank Dr. Rebecca Sheean for expert technical assistance. Proprietary antibodies against misfolded SOD1 and additional funding were provided by Amorfix Life Sciences. N.R.C. is the Canada Research Chair in Neurodegeneration and Protein Misfolding Diseases at the University of British Columbia, and is supported by donations from the Webster Foundation, the Allen T. Lambert Neural Research Fund, and the Temerty Family Foundation, and also by grants from PrioNet Canada, the Canadian Institutes of Health Research, and Biogen-Idec Corp. J.J.Y. is supported by the Motor Neurone Disease (MND) Research Institute of Australia and by National Health and Medical Research Council (NHMRC) Project Grant 1003032. B.J.T. is supported by NHMRC Project Grant 1008910 and an MND Research Institute of Australia Mick Rodger Benalla MND Research Grant. A. F. H. is an Australian Research Council Future Fellow and supported by NHMRC Program Grant 628946.