Protein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateral sclerosis

Abstract

The major pathological hallmarks of amyotrophic lateral sclerosis (ALS) are neuronal cytoplasmic inclusions (NCIs) and swollen neurites. Superoxide dismutase (SOD)-1-immunopositive NCIs are observed in patients with familial ALS (FALS), and TAR DNA-binding protein 43kDa (TDP-43)-immunopositive NCIs are found in patients with sporadic ALS (SALS). Protein disulfide isomerase (PDI) is a member of the thioredoxin superfamily and is believed to accelerate the folding of disulfide-bonded proteins by catalyzing the disulfide interchange reaction, which is the rate-limiting step during protein folding in the luminal space of the endoplasmic reticulum. Post mortem spinal cord specimens from five patients with SALS and one with FALS (I113T), and five normal controls were utilized in this immunohistochemical study. We found PDI-immunopositive swollen neurites and NCIs in the patients with ALS. Furthermore, PDI was colocalized with TDP-43 and SOD1 in NCIs. The accumulation of misfolding proteins may disturb axon transport and make swollen neurites. As the motor neuron is the longest cell in the nervous system, the motor system may selectively be disturbed. In conclusion, we assume that PDI is S-nitrosylated in the affected neurons, which inhibits its enzymatic activity and thus allows protein misfolding to occur in ALS.

Key words::

• Amyotrophic lateral sclerosis
• protein disulfide isomerase
• Lewy body-like hyaline inclusion
• misfolded protein
• unfolded protein response

Acknowledgements

We thank Kumi Kodama and Nana Kawaguchi (Department of Pharmacoepidemiology, Kyoto University) for excellent technical assistance. This work was supported in part by a research grant from Eijinkai medical group in Japan.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.