ERp57 is protective against mutant SOD1-induced cellular pathology in amyotrophic lateral sclerosis

Sonam Parakh, Cyril J. Jagaraj, Marta Vidal, Audrey M. G. Ragagnin, Emma R. Perri, Anna Konopka, Reka P. Toth, Jasmin Galper, Ian P. Blair, Colleen J. Thomas, Adam K. Walker, Shu Yang, Damian M. Spencer, Julie D. Atkin

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder and mutations in superoxide dismutase 1 (SOD1) account for 20% of familial ALS cases. The aetiology of ALS remains unclear, but protein misfolding, endoplasmic reticulum (ER) stress and neuronal apoptosis are implicated. We previously established that protein disulphide isomerase (PDIA1) is protective against ER stress and apoptosis in neuronal cells expressing mutant SOD1, and recently mutations in PDIA1 and related PDI family member endoplasmic reticulum protein 57 (ERp57/PDIA3), were associated with ALS. Here, we examined whether ERp57 is also protective against mutant SOD1 or whether distinct specificity exists amongst individual PDI family members. Neuronal cells co-expressing SOD1 and ERp57 were examined for inclusion formation, ER stress, ubiquitin proteasome system (UPS) dysfunction and apoptosis. Over-expression of ERp57 inhibited inclusion formation, ER stress, UPS dysfunction and apoptosis, whereas silencing of ERp57 expression enhanced mutant SOD1 inclusion formation, ER stress and toxicity, indicating a protective role for ERp57 against SOD1 misfolding. ERp57 also inhibited the formation of mutant SOD1 inclusions and apoptosis in primary cortical neurons, thus confirming results obtained from cell lines. ERp57 partially colocalized with TAR DNA-binding protein-43 (TDP-43)-positive inclusions in spinal cords from sporadic ALS patients, thus linking ERp57 to protein misfolding in human sporadic disease. Our results therefore imply that ERp57 has a protective role against pathological events induced by mutant SOD1 and they link ERp57 to the misfolding of TDP-43. This study therefore has implications for the design of novel therapeutics based on the activities of the PDI family of proteins.

LanguageEnglish
Pages1311-1331
Number of pages21
JournalHuman molecular genetics
Volume27
Issue number8
DOIs
Publication statusPublished - 15 Apr 2018

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Amyotrophic Lateral Sclerosis
Endoplasmic Reticulum Stress
Pathology
Apoptosis
DNA-Binding Proteins
Proteasome Endopeptidase Complex
Ubiquitin
Proteins
Protein Disulfide-Isomerases
Mutation
Superoxide Dismutase-1
Endoplasmic Reticulum
Neurodegenerative Diseases
Spinal Cord
Neurons
Cell Line

Cite this

Parakh, Sonam ; Jagaraj, Cyril J. ; Vidal, Marta ; Ragagnin, Audrey M. G. ; Perri, Emma R. ; Konopka, Anna ; Toth, Reka P. ; Galper, Jasmin ; Blair, Ian P. ; Thomas, Colleen J. ; Walker, Adam K. ; Yang, Shu ; Spencer, Damian M. ; Atkin, Julie D. / ERp57 is protective against mutant SOD1-induced cellular pathology in amyotrophic lateral sclerosis. In: Human molecular genetics. 2018 ; Vol. 27, No. 8. pp. 1311-1331.
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abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder and mutations in superoxide dismutase 1 (SOD1) account for 20{\%} of familial ALS cases. The aetiology of ALS remains unclear, but protein misfolding, endoplasmic reticulum (ER) stress and neuronal apoptosis are implicated. We previously established that protein disulphide isomerase (PDIA1) is protective against ER stress and apoptosis in neuronal cells expressing mutant SOD1, and recently mutations in PDIA1 and related PDI family member endoplasmic reticulum protein 57 (ERp57/PDIA3), were associated with ALS. Here, we examined whether ERp57 is also protective against mutant SOD1 or whether distinct specificity exists amongst individual PDI family members. Neuronal cells co-expressing SOD1 and ERp57 were examined for inclusion formation, ER stress, ubiquitin proteasome system (UPS) dysfunction and apoptosis. Over-expression of ERp57 inhibited inclusion formation, ER stress, UPS dysfunction and apoptosis, whereas silencing of ERp57 expression enhanced mutant SOD1 inclusion formation, ER stress and toxicity, indicating a protective role for ERp57 against SOD1 misfolding. ERp57 also inhibited the formation of mutant SOD1 inclusions and apoptosis in primary cortical neurons, thus confirming results obtained from cell lines. ERp57 partially colocalized with TAR DNA-binding protein-43 (TDP-43)-positive inclusions in spinal cords from sporadic ALS patients, thus linking ERp57 to protein misfolding in human sporadic disease. Our results therefore imply that ERp57 has a protective role against pathological events induced by mutant SOD1 and they link ERp57 to the misfolding of TDP-43. This study therefore has implications for the design of novel therapeutics based on the activities of the PDI family of proteins.",
author = "Sonam Parakh and Jagaraj, {Cyril J.} and Marta Vidal and Ragagnin, {Audrey M. G.} and Perri, {Emma R.} and Anna Konopka and Toth, {Reka P.} and Jasmin Galper and Blair, {Ian P.} and Thomas, {Colleen J.} and Walker, {Adam K.} and Shu Yang and Spencer, {Damian M.} and Atkin, {Julie D.}",
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ERp57 is protective against mutant SOD1-induced cellular pathology in amyotrophic lateral sclerosis. / Parakh, Sonam; Jagaraj, Cyril J.; Vidal, Marta; Ragagnin, Audrey M. G.; Perri, Emma R.; Konopka, Anna; Toth, Reka P.; Galper, Jasmin; Blair, Ian P.; Thomas, Colleen J.; Walker, Adam K.; Yang, Shu; Spencer, Damian M.; Atkin, Julie D.

In: Human molecular genetics, Vol. 27, No. 8, 15.04.2018, p. 1311-1331.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - ERp57 is protective against mutant SOD1-induced cellular pathology in amyotrophic lateral sclerosis

AU - Parakh, Sonam

AU - Jagaraj, Cyril J.

AU - Vidal, Marta

AU - Ragagnin, Audrey M. G.

AU - Perri, Emma R.

AU - Konopka, Anna

AU - Toth, Reka P.

AU - Galper, Jasmin

AU - Blair, Ian P.

AU - Thomas, Colleen J.

AU - Walker, Adam K.

AU - Yang, Shu

AU - Spencer, Damian M.

AU - Atkin, Julie D.

PY - 2018/4/15

Y1 - 2018/4/15

N2 - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder and mutations in superoxide dismutase 1 (SOD1) account for 20% of familial ALS cases. The aetiology of ALS remains unclear, but protein misfolding, endoplasmic reticulum (ER) stress and neuronal apoptosis are implicated. We previously established that protein disulphide isomerase (PDIA1) is protective against ER stress and apoptosis in neuronal cells expressing mutant SOD1, and recently mutations in PDIA1 and related PDI family member endoplasmic reticulum protein 57 (ERp57/PDIA3), were associated with ALS. Here, we examined whether ERp57 is also protective against mutant SOD1 or whether distinct specificity exists amongst individual PDI family members. Neuronal cells co-expressing SOD1 and ERp57 were examined for inclusion formation, ER stress, ubiquitin proteasome system (UPS) dysfunction and apoptosis. Over-expression of ERp57 inhibited inclusion formation, ER stress, UPS dysfunction and apoptosis, whereas silencing of ERp57 expression enhanced mutant SOD1 inclusion formation, ER stress and toxicity, indicating a protective role for ERp57 against SOD1 misfolding. ERp57 also inhibited the formation of mutant SOD1 inclusions and apoptosis in primary cortical neurons, thus confirming results obtained from cell lines. ERp57 partially colocalized with TAR DNA-binding protein-43 (TDP-43)-positive inclusions in spinal cords from sporadic ALS patients, thus linking ERp57 to protein misfolding in human sporadic disease. Our results therefore imply that ERp57 has a protective role against pathological events induced by mutant SOD1 and they link ERp57 to the misfolding of TDP-43. This study therefore has implications for the design of novel therapeutics based on the activities of the PDI family of proteins.

AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder and mutations in superoxide dismutase 1 (SOD1) account for 20% of familial ALS cases. The aetiology of ALS remains unclear, but protein misfolding, endoplasmic reticulum (ER) stress and neuronal apoptosis are implicated. We previously established that protein disulphide isomerase (PDIA1) is protective against ER stress and apoptosis in neuronal cells expressing mutant SOD1, and recently mutations in PDIA1 and related PDI family member endoplasmic reticulum protein 57 (ERp57/PDIA3), were associated with ALS. Here, we examined whether ERp57 is also protective against mutant SOD1 or whether distinct specificity exists amongst individual PDI family members. Neuronal cells co-expressing SOD1 and ERp57 were examined for inclusion formation, ER stress, ubiquitin proteasome system (UPS) dysfunction and apoptosis. Over-expression of ERp57 inhibited inclusion formation, ER stress, UPS dysfunction and apoptosis, whereas silencing of ERp57 expression enhanced mutant SOD1 inclusion formation, ER stress and toxicity, indicating a protective role for ERp57 against SOD1 misfolding. ERp57 also inhibited the formation of mutant SOD1 inclusions and apoptosis in primary cortical neurons, thus confirming results obtained from cell lines. ERp57 partially colocalized with TAR DNA-binding protein-43 (TDP-43)-positive inclusions in spinal cords from sporadic ALS patients, thus linking ERp57 to protein misfolding in human sporadic disease. Our results therefore imply that ERp57 has a protective role against pathological events induced by mutant SOD1 and they link ERp57 to the misfolding of TDP-43. This study therefore has implications for the design of novel therapeutics based on the activities of the PDI family of proteins.

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