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. Atkin

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Number of pages15
JournalCellular and Molecular Life Sciences
DOIs
Publication statusE-pub ahead of print - 4 Dec 2019

Fingerprint

Endoplasmic Reticulum Stress
Amyotrophic Lateral Sclerosis
Endoplasmic Reticulum
Protein Transport
Endoplasmic Reticulum-Associated Degradation
Ubiquitins
Frontotemporal Dementia
Golgi Apparatus
Neurodegenerative Diseases
Spinal Cord
Homeostasis
Mutation
Genes
Frontotemporal Dementia With Motor Neuron Disease

Keywords

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

Cite this

@article{7e38404b790f4a92b34d9f368035bdec,
title = "Amyotrophic lateral sclerosis-linked UBQLN2 mutants inhibit endoplasmic reticulum to Golgi transport, leading to Golgi fragmentation and ER stress",
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 stress, ER-Golgi trafficking, Golgi fragmentation, Ubiquilin-2, Unfolded protein response",
author = "Mark Halloran and Ragagnin, {Audrey M.G.} and Marta Vidal and Sonam Parakh and Shu Yang and Benjamin Heng and Natalie Grima and Hamideh Shahheydari and Kai-Ying Soo and Ian Blair and Guillemin, {Gilles J.} and Vinod Sundaramoorthy and Atkin, {Julie D.}",
year = "2019",
month = "12",
day = "4",
doi = "10.1007/s00018-019-03394-w",
language = "English",
journal = "Cellular and Molecular Life Sciences",
issn = "1420-682X",
publisher = "Springer, Springer Nature",

}

Amyotrophic lateral sclerosis-linked UBQLN2 mutants inhibit endoplasmic reticulum to Golgi transport, leading to Golgi fragmentation and ER stress. / Halloran, Mark; Ragagnin, Audrey M.G.; Vidal, Marta; Parakh, Sonam; Yang, Shu; Heng, Benjamin; Grima, Natalie; Shahheydari, Hamideh; Soo, Kai-Ying; Blair, Ian; Guillemin, Gilles J.; Sundaramoorthy, Vinod; Atkin, Julie D.

In: Cellular and Molecular Life Sciences, 04.12.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Amyotrophic lateral sclerosis-linked UBQLN2 mutants inhibit endoplasmic reticulum to Golgi transport, leading to Golgi fragmentation and ER stress

AU - Halloran, Mark

AU - Ragagnin, Audrey M.G.

AU - Vidal, Marta

AU - Parakh, Sonam

AU - Yang, Shu

AU - Heng, Benjamin

AU - Grima, Natalie

AU - Shahheydari, Hamideh

AU - Soo, Kai-Ying

AU - Blair, Ian

AU - Guillemin, Gilles J.

AU - Sundaramoorthy, Vinod

AU - Atkin, Julie D.

PY - 2019/12/4

Y1 - 2019/12/4

N2 - 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.

AB - 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.

KW - Amyotrophic lateral sclerosis

KW - ER stress

KW - ER-Golgi trafficking

KW - Golgi fragmentation

KW - Ubiquilin-2

KW - Unfolded protein response

UR - http://www.scopus.com/inward/record.url?scp=85076028782&partnerID=8YFLogxK

U2 - 10.1007/s00018-019-03394-w

DO - 10.1007/s00018-019-03394-w

M3 - Article

JO - Cellular and Molecular Life Sciences

T2 - Cellular and Molecular Life Sciences

JF - Cellular and Molecular Life Sciences

SN - 1420-682X

ER -