Amyotrophic lateral sclerosis-linked UBQLN2 mutants inhibit endoplasmic reticulum to Golgi transport, leading to Golgi fragmentation and ER stress

  • Mark Halloran
  • Audrey M. G. Ragagnin
  • Marta Vidal
  • Sonam Parakh
  • Shu Yang
  • Benjamin Heng
  • Natalie Grima
  • Hamideh Shahheydari
  • Kai-Ying Soo
  • Ian Blair
  • Gilles J. Guillemin
  • Vinod Sundaramoorthy
  • Julie D. AtkinEmail author
Original Article


Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases that are related genetically and pathologically. Mutations in the UBQLN2 gene, encoding the ubiquitin-like protein ubiquilin2, are associated with familial ALS/FTD, but the pathophysiological mechanisms remain unclear. Here, we demonstrate that ALS/FTD UBQLN2 mutants P497H and P506T inhibit protein transport from the endoplasmic reticulum (ER) to the Golgi apparatus in neuronal cells. In addition, we observed that Sec31-positive ER exit sites are clustered in UBQLN2T487I patient spinal cord tissues. Both the ER–Golgi intermediate (ERGIC) compartment and the Golgi become disorganised and fragmented. This activates ER stress and inhibits ER-associated degradation. Hence, this study highlights perturbations in secretory protein trafficking and ER homeostasis as pathogenic mechanisms associated with ALS/FTD-associated forms of UBQLN2.


Amyotrophic lateral sclerosis ER-Golgi trafficking ER stress Ubiquilin-2 Unfolded protein response Golgi fragmentation 


Author contributions

All authors contributed to this article. JDA conceived and directed the project. JDA, MH, AMGR, K-YS, and VS designed the experiments. MH, AMGR designed and prepared the UBQLN2 constructs. HS helped to design the UBQLN2 constructs. MH performed and analysed experiments in Neuro2A cells (ER–Golgi transport, Golgi and ERGIC fragmentation, ER stress). AMGR performed and analysed the ERAD assay. MV, BH and SP performed and analysed experiments in human primary neurons. NG and SY performed and analysed experiments in human sections. MH, AMGR and JDA wrote, edited and revised the manuscript. All authors discussed results and commented on the manuscript.

Supplementary material

18_2019_3394_MOESM1_ESM.docx (2.8 mb)
Supplementary material 1 (DOCX 2875 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Mark Halloran
    • 1
  • Audrey M. G. Ragagnin
    • 1
  • Marta Vidal
    • 1
  • Sonam Parakh
    • 1
  • Shu Yang
    • 1
  • Benjamin Heng
    • 1
  • Natalie Grima
    • 1
  • Hamideh Shahheydari
    • 1
  • Kai-Ying Soo
    • 1
  • Ian Blair
    • 1
  • Gilles J. Guillemin
    • 1
  • Vinod Sundaramoorthy
    • 1
  • Julie D. Atkin
    • 1
    • 2
    Email author
  1. 1.Department of Biomedical Sciences, Faculty of Medicine and Health SciencesMacquarie UniversitySydneyAustralia
  2. 2.Department of Biochemistry and Genetics, La Trobe Institute for Molecular ScienceLa Trobe UniversityMelbourneAustralia

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