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

doi:10.1007/s00018-019-03394-w

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

27 Citations (Scopus)

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 UBQLN2^T487I 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.

Original language	English
Pages (from-to)	3859-3873
Number of pages	15
Journal	Cellular and Molecular Life Sciences
Volume	77
Issue number	19
Early online date	4 Dec 2019
DOIs	https://doi.org/10.1007/s00018-019-03394-w
Publication status	Published - Oct 2020

Keywords

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

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10.1007/s00018-019-03394-w

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Halloran, M., Ragagnin, A. M. G., Vidal, M., Parakh, S., Yang, S., Heng, B., Grima, N., Shahheydari, H., Soo, K.-Y., Blair, I., Guillemin, G. J., Sundaramoorthy, V., & Atkin, J. D. (2020). Amyotrophic lateral sclerosis-linked UBQLN2 mutants inhibit endoplasmic reticulum to Golgi transport, leading to Golgi fragmentation and ER stress. Cellular and Molecular Life Sciences, 77(19), 3859-3873. https://doi.org/10.1007/s00018-019-03394-w

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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.}",

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doi = "10.1007/s00018-019-03394-w",

language = "English",

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Halloran, M, Ragagnin, AMG, Vidal, M, Parakh, S , Yang, S , Heng, B , Grima, N, Shahheydari, H, Soo, K-Y, Blair, I, Guillemin, GJ, Sundaramoorthy, V & Atkin, JD 2020, 'Amyotrophic lateral sclerosis-linked UBQLN2 mutants inhibit endoplasmic reticulum to Golgi transport, leading to Golgi fragmentation and ER stress', Cellular and Molecular Life Sciences, vol. 77, no. 19, pp. 3859-3873. https://doi.org/10.1007/s00018-019-03394-w

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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 - 2020/10

Y1 - 2020/10

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

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KW - Unfolded protein response

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SN - 1420-682X

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EP - 3873

JO - Cellular and Molecular Life Sciences

JF - Cellular and Molecular Life Sciences

IS - 19

ER -

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

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