title: 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.
authors: Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Japan.
authors: Yasuyuki
authors: Y
authors: Honjo
authors: Satoshi
authors: S
authors: Kaneko
authors: Hidefumi
authors: H
authors: Ito
authors: Tomohisa
authors: T
authors: Horibe
authors: Masato
authors: M
authors: Nagashima
authors: Masataka
authors: M
authors: Nakamura
authors: Kengo
authors: K
authors: Fujita
authors: Ryosuke
authors: R
authors: Takahashi
authors: Hirofumi
authors: H
authors: Kusaka
authors: Koji
authors: K
authors: Kawakami
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000473:pathology*; D000818:Animals; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000201:enzymology* / Q000473:pathology*; D019704:Protein Disulfide-Isomerases / Q000737:chemistry / Q000378:metabolism*; D017510:Protein Folding
chemical_list: D004268:DNA-Binding Proteins; D019704:Protein Disulfide-Isomerases