Acta Neuropathologica

, Volume 130, Issue 5, pp 679–697 | Cite as

Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS

  • Kai Y. Soo
  • Mark Halloran
  • Vinod Sundaramoorthy
  • Sonam Parakh
  • Reka P. Toth
  • Katherine A. Southam
  • Catriona A. McLean
  • Peter Lock
  • Anna King
  • Manal A. Farg
  • Julie D. AtkinEmail author
Original Paper


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 inhibited the incorporation of secretory protein cargo into COPII vesicles as they bud from the ER, and inhibited transport from ER to the ER–Golgi intermediate (ERGIC) compartment. TDP-43 was detected on the cytoplasmic face of the ER membrane, whereas FUS was present within the ER, suggesting that transport is inhibited from the cytoplasm by mutant TDP-43, and from the ER by mutant FUS. In contrast, mutant SOD1 destabilised microtubules and inhibited transport from the ERGIC compartment to Golgi, but not from ER to ERGIC. Rab1 performs multiple roles in ER–Golgi transport, and over-expression of Rab1 restored ER–Golgi transport, and prevented ER stress, mSOD1 inclusion formation and induction of apoptosis, in cells expressing mutant TDP-43, FUS or SOD1. Rab1 also co-localised extensively with mutant TDP-43, FUS and SOD1 in neuronal cells, and Rab1 formed inclusions in motor neurons of spinal cords from sporadic ALS patients, which were positive for ubiquitinated TDP-43, implying that Rab1 is misfolded and dysfunctional in sporadic disease. These results demonstrate that ALS-mutant forms of TDP-43, FUS, and SOD1 all perturb protein transport in the early secretory pathway, between ER and Golgi compartments. These data also imply that restoring Rab1-mediated ER–Golgi transport is a novel therapeutic target in ALS.


TDP-43 FUS SOD1 ER–Golgi transport Amyotrophic lateral sclerosis 



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].

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All applicable international, national and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Supplementary material

401_2015_1468_MOESM1_ESM.pdf (2.3 mb)
Supplementary material 1 (PDF 2320 kb)


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© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Kai Y. Soo
    • 1
  • Mark Halloran
    • 1
    • 2
  • Vinod Sundaramoorthy
    • 1
    • 2
  • Sonam Parakh
    • 1
    • 2
  • Reka P. Toth
    • 2
  • Katherine A. Southam
    • 3
  • Catriona A. McLean
    • 4
    • 5
  • Peter Lock
    • 1
  • Anna King
    • 6
  • Manal A. Farg
    • 1
  • Julie D. Atkin
    • 1
    • 2
    Email author
  1. 1.Department of Biochemistry and Genetics, La Trobe Institute for Molecular ScienceLa Trobe UniversityBundooraAustralia
  2. 2.Department of Biomedical Sciences, Faculty of Medicine and Health ScienceMacquarie UniversityNorth RydeAustralia
  3. 3.Menzies Research Institute TasmaniaUniversity of TasmaniaHobartAustralia
  4. 4.Department of Anatomical PathologyAlfred HospitalPrahranAustralia
  5. 5.Department of Medicine, Central Clinical SchoolMonash UniversityClaytonAustralia
  6. 6.Wicking Dementia Research and Education CentreUniversity of TasmaniaHobartAustralia

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