Copper chaperone for superoxide dismutase co-aggregates with superoxide dismutase 1 (SOD1) in neuronal Lewy body-like hyaline inclusions: an immunohistochemical study on familial amyotrophic lateral sclerosis with SOD1 gene mutation

Kato, Shinsuke; Sumi-Akamaru, Hisae; Fujimura, Harutoshi; Sakoda, Saburo; Kato, Masako; Hirano, Atsushi; Takikawa, Miki; Ohama, Eisaku

doi:10.1007/s004010000355

Cited by 49 publications

(19 citation statements)

References 15 publications

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“…In contrast, however, copper levels have not been reported in SOD1 -ALS cases, and little consensus has been reached on any changes of the proteins maintaining homeostasis of intracellular copper ions in human ALS cases. For example, histopathological examination of fALS cases with SOD1 mutations (three cases with A4V and two cases with L126Z) has shown that CCS is co-aggregated with mutant SOD1 in the neuronal Lewy body-like hyaline inclusions in the spinal cords [ 62 ]. Another report has, however, described no staining of inclusions with anti-CCS antibody in a fALS case with A4V mutation as well as most of sporadic ALS cases [ 63 ].…”

Section: Copper Homeostasis In Human Alsmentioning

confidence: 99%

Copper Homeostasis as a Therapeutic Target in Amyotrophic Lateral Sclerosis with SOD1 Mutations

Tokuda

Furukawa

2016

IJMS

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Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease affecting both upper and lower motor neurons, and currently, there is no cure or effective treatment. Mutations in a gene encoding a ubiquitous antioxidant enzyme, Cu,Zn-superoxide dismutase (SOD1), have been first identified as a cause of familial forms of ALS. It is widely accepted that mutant SOD1 proteins cause the disease through a gain in toxicity but not through a loss of its physiological function. SOD1 is a major copper-binding protein and regulates copper homeostasis in the cell; therefore, a toxicity of mutant SOD1 could arise from the disruption of copper homeostasis. In this review, we will briefly review recent studies implying roles of copper homeostasis in the pathogenesis of SOD1-ALS and highlight the therapeutic interventions focusing on pharmacological as well as genetic regulations of copper homeostasis to modify the pathological process in SOD1-ALS.

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Section: Copper Homeostasis In Human Alsmentioning

confidence: 99%

Copper Homeostasis as a Therapeutic Target in Amyotrophic Lateral Sclerosis with SOD1 Mutations

Tokuda

Furukawa

2016

IJMS

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“…Only three mutations that would be predicted to produce mRNAs that would be degraded by nonsense mediated decay pathways are reported in the database [4], and the etiological significance of these mutations is uncertain. A pathologic feature of SOD1-linked fALS that is commonly, but not uniformly found, is the accumulation of SOD1 immuno-reactive inclusions in surviving spinal motor neurons [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. Multiple studies have demonstrated that fALS mutant SOD1 expressed in cultured cells is generally more prone to misfold and aggregate than wild-type [5,[29][30][31][32][33], and aggregation of mutant SOD1 appears to be a critical factor in disease pathogenesis [32,34,35].…”

Section: Introductionmentioning

confidence: 99%

Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection

et al. 2020

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Mutations in Cu/Zn superoxide dismutase 1 (SOD1) associated with familial amyotrophic lateral sclerosis cause the protein to aggregate via a prion-like process in which soluble molecules are recruited to aggregates by conformational templating. These misfolded SOD1 proteins can propagate aggregation-inducing conformations across cellular membranes. Prior studies demonstrated that mutation of a Trp (W) residue at position 32 to Ser (S) suppresses the propagation of misfolded conformations between cells, whereas other studies have shown that mutation of Trp 32 to Phe (F), or Cys 111 to Ser, can act in cis to attenuate aggregation of mutant SOD1. By expressing mutant SOD1 fused with yellow fluorescent protein (YFP), we compared the relative ability of these mutations to modulate the formation of inclusions by ALS-mutant SOD1 (G93A and G85R). Only mutation of Trp 32 to Ser persistently reduced the formation of the amorphous inclusions that form in these cells, consistent with the idea that a Ser at position 32 inhibits templated propagation of aggregation prone conformations. To further test this idea, we produced aggregated fibrils of recombinant SOD1-W32S in vitro and injected them into the spinal cords of newborn mice expressing G85R-SOD1: YFP. The injected mice developed an earlier onset paralysis with a frequency similar to mice injected with WT SOD1 fibrils, generating a strain of misfolded SOD1 that produced highly fibrillar inclusion pathology. These findings suggest that the effect of Trp 32 in modulating the propagation of misfolded SOD1 conformations may be dependent upon the "strain" of the conformer that is propagating.

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“…Sections were subjected to routine staining including hematoxylin and eosin (HE), Klüver-Barrera (KB), Holzer, and modified Hirano-Bielschowsky stains. Representative paraffin sections were used for the immunohistochemical staining with the following primary antibodies: (i) affinity-purified rabbit polyclonal anti-human iNOS (diluted 1:1000 in 1% bovine serum albumincontaining phosphate-buffered saline [BSA-PBS], pH7.4; gifted by Dr. Esumi) 14,15 (ii) rabbit polyclonal anti-human superoxide dismutase 1 (SOD1) (diluted 1:10 000)[BSA-PBS], pH7.4; gifted by Dr. Asayama [15][16][17][18][19][20][21] (iii) mouse monoclonal anti-human SOD1 (concentration: 3 μg/mL; MBL, Nagoya, Japan); (iv) mouse IgG 1 monoclonal anti-glial fibrillary acidic protein (GFAP) (high-performance, readyto-use; BioGenex, San Ramon, CA, USA); and (v) mouse monoclonal anti-PrP clone 3F4 (diluted 1:500; Senetek PLC, St Louis, MO, USA). The specificity and effectiveness for their use in immunohistochemical detection on human materials have been previously documented.…”

Section: Histopathology and Immunohistochemistrymentioning

confidence: 99%

“…The specificity and effectiveness for their use in immunohistochemical detection on human materials have been previously documented. 15,[17][18][19][20][21][22][23][24] Sections were deparaffinized, and endogenous peroxidase activity was quenched by incubation for 30 min with 0.3% H 2 O 2 . To enhance PrP immunoreactivity, some sections were pretreated with 100% formic acid and hydrolytic autoclaving.…”

Section: Histopathology and Immunohistochemistrymentioning

confidence: 99%

Immunohistochemical and ultrastructural evidence for the pathogenesis of white matter degeneration in patients with panencephalopathic‐type Creutzfeldt–Jakob disease: Inducible nitric oxide synthase overexpression in bizarre astrocytes

et al. 2020

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Excessive production of nitric oxide (NO) due to the overinduction of inducible nitric oxide synthase (iNOS) has a severe cytotoxic effect, which may relate to the pathogenesis of neurodegenerative disorders. In this study, we report the novel finding that iNOS is overinduced in a large number of bizarre astrocytes in the white matter of patients with panencephalopathic (PE)‐type Creutzfeldt–Jakob disease (CJD). This study was carried out on brain tissue from seven patients with PE‐type CJD. As controls, 12 normal individuals and nine patients with cerebral infarction were examined. We identified a large number of bizarre astrocytes in the degenerative cerebral white matter in PE‐type CJD. Using immunohistochemistry, only bizarre astrocytes in PE‐type CJD showed strong immunoreactivity for both iNOS and superoxide dismutase 1 (SOD1). Ultrastructural examination demonstrated that these bizarre astrocytes contained many free polyribosome‐like granules. No significant iNOS immunoreactivity was observed in either the astrocytes of patients with cerebral infarcts or in the normal controls. This study suggests that the iNOS‐overexpressing astrocytes, especially iNOS‐overexpressing bizarre astrocytes, could play an important role in the development of white matter lesions in PE‐type CJD. Our data also suggest that the bizarre astrocytes could be protecting themselves from the cytotoxicity of NO by producing SOD1. These immunohistochemical findings are supported by the ultrastructural observation of numerous polyribosome granules restricted to the cytoplasm of these bizarre astrocytes.

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Copper chaperone for superoxide dismutase co-aggregates with superoxide dismutase 1 (SOD1) in neuronal Lewy body-like hyaline inclusions: an immunohistochemical study on familial amyotrophic lateral sclerosis with SOD1 gene mutation

Cited by 49 publications

References 15 publications

Copper Homeostasis as a Therapeutic Target in Amyotrophic Lateral Sclerosis with SOD1 Mutations

Copper Homeostasis as a Therapeutic Target in Amyotrophic Lateral Sclerosis with SOD1 Mutations

Tryptophan residue 32 in human Cu-Zn superoxide dismutase modulates prion-like propagation and strain selection

Immunohistochemical and ultrastructural evidence for the pathogenesis of white matter degeneration in patients with panencephalopathic‐type Creutzfeldt–Jakob disease: Inducible nitric oxide synthase overexpression in bizarre astrocytes

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