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.

journal_name

Neuroreport

journal_title

Neuroreport

authors

Chang RC,Parakh S,Coates JR,Long S,Atkin JD

doi

10.1097/WNR.0000000000001151

subject

Has Abstract

pub_date

2019-01-02 00:00:00

pages

8-13

issue

1

eissn

0959-4965

issn

1473-558X

journal_volume

30

pub_type

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