Amyotrophic lateral sclerosis-linked UBQLN2 mutants inhibit endoplasmic reticulum to Golgi transport, leading to Golgi f
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Amyotrophic lateral sclerosis‑linked UBQLN2 mutants inhibit endoplasmic reticulum to Golgi transport, leading to Golgi fragmentation and ER stress Mark Halloran1 · Audrey M. G. Ragagnin1 · Marta Vidal1 · Sonam Parakh1 · Shu Yang1 · Benjamin Heng1 · Natalie Grima1 · Hamideh Shahheydari1 · Kai‑Ying Soo1 · Ian Blair1 · Gilles J. Guillemin1 · Vinod Sundaramoorthy1 · Julie D. Atkin1,2 Received: 9 April 2019 / Revised: 28 October 2019 / Accepted: 22 November 2019 © Springer Nature Switzerland AG 2019
Abstract 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. Keywords Amyotrophic lateral sclerosis · ER-Golgi trafficking · ER stress · Ubiquilin-2 · Unfolded protein response · Golgi fragmentation
Introduction Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons, leading to muscular weakness, paralysis and death within 3–5 years of initial diagnosis [1–3]. Approximately 10% of all ALS cases are familial (fALS), caused by mutations in ~ 25 different genes including UBQLN2, encoding ubiquilin 2 (UBQLN2), Mark Halloran and Audrey M. G. Ragagnin contributed equally. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-019-03394-w) contains supplementary material, which is available to authorized users. * Julie D. Atkin [email protected] 1
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, Australia
2
a member of the ubiquitin-like protein family that functions in proteosomal degradation. In contrast, the remaining 90% of ALS cases arise sporadically (sporadic ALS, sALS) [1, 2, 4]. ALS is linked genetically and pathologically with frontotemporal dementia (FTD) [5] and mutations in UBQLN2 cause dominantly inherited chromosome-X-linked juvenile and adult-onset fALS, ALS-FTD and FTD [6–10]. Disturbances to proteostasis, including defects in cellular trafficking, are increasingly impli
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