Journal article
Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS
KY Soo, M Halloran, V Sundaramoorthy, S Parakh, RP Toth, KA Southam, CA McLean, P Lock, A King, MA Farg, JD Atkin
Acta Neuropathologica | SPRINGER | Published : 2015
Abstract
Several diverse proteins are linked genetically/pathologically to neurodegeneration in amyotrophic lateral sclerosis (ALS) including SOD1, TDP-43 and FUS. Using a variety of cellular and biochemical techniques, we demonstrate that ALS-associated mutant TDP-43, FUS and SOD1 inhibit protein transport between the endoplasmic reticulum (ER) and Golgi apparatus in neuronal cells. ER–Golgi transport was also inhibited in embryonic cortical and motor neurons obtained from a widely used animal model (SOD1G93A mice), validating this mechanism as an early event in disease. Each protein inhibited transport by distinct mechanisms, but each process was dependent on Rab1. Mutant TDP-43 and mutant FUS both..
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Funding Acknowledgements
We thank Professor Malcolm Horne and Professor Phillip Nagley for helpful discussions. Human patient and control lumbar region tissues were received from the Victorian Brain Bank Network, supported by University of Melbourne, Mental Health Research Institute of Victoria, and Victorian Forensic Institute of Medicine and funded by Neurosciences Australia and the National Health and Medical Research Council of Australia (NHMRC). This work was supported by NHMRC Project grants [# 1006141, 1030513 to JA], Bethlehem Griffiths Research Foundation, and Angie Cunningham Laugh to Cure MND grant [to JDA and KYS].