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Canine SOD1 harboring E40K or T18S mutations promotes protein aggregation without reducing the global structural stability

Canine SOD1 harboring E40K or T18S mutations promotes protein aggregation without reducing the global structural stability

Authors :
Shintaro Kimura
Yuji O. Kamatari
Yukina Kuwahara
Hideaki Hara
Osamu Yamato
Sadatoshi Maeda
Hiroaki Kamishina
Ryo Honda
Source :
PeerJ, Vol 8, p e9512 (2020)
Publication Year :
2020
Publisher :
PeerJ Inc., 2020.

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease associated with aggregation of superoxide dismutase 1 (SOD1) protein. More than 160 mutations in human SOD1 have been identified in familial ALS and extensively characterized in previous studies. Here, we investigated the effects of T18S and E40K mutations on protein aggregation of canine SOD1. These two mutations are exclusively found in canine degenerative myelopathy (an ALS-like neurodegenerative disease in dogs), whose phenotype is unknown at the level of protein folding. Interestingly, the T18S and E40K mutations did not alter far-UV CD spectrum, enzymatic activity, or global structural stability of canine SOD1. However, thioflavin-T assay and transmission electron microscopy analysis revealed that these mutations promote formation of fibrous aggregates, in particular in the Cu2+/Zn2+-unbound state. These evidence suggested that the T18S and E40K mutations promote protein aggregation through a unique mechanism, possibly involving destabilization of the local structure, reduction of net negative charge, or production of disulfide-linked oligomers.

Details

Language :
English
ISSN :
21678359
Volume :
8
Database :
Directory of Open Access Journals
Journal :
PeerJ
Publication Type :
Academic Journal
Accession number :
edsdoj.822beba6fee145c38d556231b33bdc9d
Document Type :
article
Full Text :
https://doi.org/10.7717/peerj.9512