Protein disulphide isomerase is associated with mutant SOD1 in canine degenerative myelopathy

Rachel C. Chang, Sonam Parakh, Joan R. Coates, Sam Long, Julie D. Atkin

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Canine degenerative myelopathy (DM) is a fatal neurodegenerative disorder prevalent in the canine population. It may represent a unique, naturally occurring disease model for human amyotrophic lateral sclerosis (ALS) because of similar clinical signs and association with superoxide dismutase 1 gene (SOD1) mutations. Misfolded SOD1 aggregates and endoplasmic reticulum (ER) stress are major pathophysiological features associated with ALS. Interestingly, an ER foldase, protein disulphide isomerase (PDI) is upregulated during ALS and it co-localizes with SOD1 inclusions in ALS patient tissues. Furthermore, mutations in the gene encoding PDI were recently associated with ALS. Given the genetic similarity between DM and ALS, we investigated whether ER stress and PDI were associated with DM. Protein extracts from spinal cord tissue of DM-affected dogs bearing a SOD1 mutation were examined for ER stress by western blotting. Immunohistochemical staining was also carried out to examine co-localization between endogenous PDI and SOD1 inclusions in spinal cord tissues of dogs affected with DM. PDI and CHOP, the proapoptotic protein induced during ER stress, were significantly upregulated in DM-affected dogs compared with controls. Furthermore, PDI co-localized with intracellular SOD1 aggregates in DM-affected dogs in all motor neurons examined, indicating that PDI may be a cellular defence mechanism against SOD1 misfolding in DM. Our results imply that ER stress is induced in DM-affected dogs; hence, it is a common pathological mechanism associated with both ALS and DM. The possibility that PDI may be a therapeutic target to inhibit SOD1 aggregation in DM dogs is also raised by this study.

LanguageEnglish
Pages8-13
Number of pages6
JournalNeuroReport
Volume30
Issue number1
DOIs
Publication statusPublished - 2 Jan 2019

Fingerprint

Protein Disulfide-Isomerases
Spinal Cord Diseases
Canidae
Amyotrophic Lateral Sclerosis
Endoplasmic Reticulum Stress
Genes
Dogs
Mutation
Spinal Cord
Superoxide Dismutase-1
Proteins
Motor Neurons
Heat-Shock Proteins
Endoplasmic Reticulum
Neurodegenerative Diseases
Western Blotting

Keywords

  • amyotrophic lateral sclerosis
  • dog
  • spinal cord
  • superoxide dismutase 1

Cite this

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title = "Protein disulphide isomerase is associated with mutant SOD1 in canine degenerative myelopathy",
abstract = "Canine degenerative myelopathy (DM) is a fatal neurodegenerative disorder prevalent in the canine population. It may represent a unique, naturally occurring disease model for human amyotrophic lateral sclerosis (ALS) because of similar clinical signs and association with superoxide dismutase 1 gene (SOD1) mutations. Misfolded SOD1 aggregates and endoplasmic reticulum (ER) stress are major pathophysiological features associated with ALS. Interestingly, an ER foldase, protein disulphide isomerase (PDI) is upregulated during ALS and it co-localizes with SOD1 inclusions in ALS patient tissues. Furthermore, mutations in the gene encoding PDI were recently associated with ALS. Given the genetic similarity between DM and ALS, we investigated whether ER stress and PDI were associated with DM. Protein extracts from spinal cord tissue of DM-affected dogs bearing a SOD1 mutation were examined for ER stress by western blotting. Immunohistochemical staining was also carried out to examine co-localization between endogenous PDI and SOD1 inclusions in spinal cord tissues of dogs affected with DM. PDI and CHOP, the proapoptotic protein induced during ER stress, were significantly upregulated in DM-affected dogs compared with controls. Furthermore, PDI co-localized with intracellular SOD1 aggregates in DM-affected dogs in all motor neurons examined, indicating that PDI may be a cellular defence mechanism against SOD1 misfolding in DM. Our results imply that ER stress is induced in DM-affected dogs; hence, it is a common pathological mechanism associated with both ALS and DM. The possibility that PDI may be a therapeutic target to inhibit SOD1 aggregation in DM dogs is also raised by this study.",
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Protein disulphide isomerase is associated with mutant SOD1 in canine degenerative myelopathy. / Chang, Rachel C.; Parakh, Sonam; Coates, Joan R.; Long, Sam; Atkin, Julie D.

In: NeuroReport, Vol. 30, No. 1, 02.01.2019, p. 8-13.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Protein disulphide isomerase is associated with mutant SOD1 in canine degenerative myelopathy

AU - Chang,Rachel C.

AU - Parakh,Sonam

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AU - Long,Sam

AU - Atkin,Julie D.

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