Pyrimethamine significantly lowers cerebrospinal fluid Cu/Zn superoxide dismutase in amyotrophic lateral sclerosis patients with <i>SOD1</i> mutations

Lange, Dale J.; Shahbazi, Mona; Silani, Vincenzo; Ludolph, Albert C.; Weishaupt, Jochen H.; Ajroud‐Driss, Senda; Fields, Kara G.; Remanan, Rahul; Appel, Stanley H.; Morelli, Claudia; Doretti, Alberto; Maderna, Luca; Messina, Stefano; Weiland, Ulrike; Marklund, Stefan L.; Andersen, Peter M.

doi:10.1002/ana.24950

Cited by 39 publications

(31 citation statements)

References 34 publications

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“…More than 185 mutations in SOD1 have been reported to date [13]. Multiple efforts have focused on targeted therapeutic approaches for SOD1 -related ALS (ClinicalTrials.gov: NCT01041222: SOD1Rx [14]; NCT00706147: Arimoclomol [15]; NCT01083667: Pyrimethamine [16]).…”

Section: Introductionmentioning

confidence: 99%

Better survival in female SOD1-mutant patients with ALS: a study of SOD1-related natural history

Tang

Liu

et al. 2019

Transl Neurodegener

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BackgroundSOD1 mutations are the most common cause of amyotrophic lateral sclerosis (ALS) in non-Caucasian patients. Detailed natural history profiles of SOD1-mutant patients will be beneficial for the strategy and interpretation of future SOD1-targeted clinical practice.MethodsMutational distribution, age at onset (AAO), site of onset, diagnostic delay, disease progression (rate of ALSFRS-R decrease, ΔFS) and survival were analysed. Further comparisons between heredity of disease, gender, and mutations were performed.ResultsSixty-six cases with 43 SOD1 mutations were included and analysed, with p.His47Arg as the leading mutation and seven novel variants identified. The mean (SD) AAO was 43.92 years (9.24) for all subjects, with a significant difference between patients carrying mutations in exon 2 (n = 24,46.83, 8.31) and exon 4 (n = 18, 37.75, 7.67) (p = 0.002). The median (IQR) diagnostic delay from symptom onset was 14.50 (6.00–36.50) months for all SOD1-mutant patients, 9.50 (4.75–24.25) months for males and 24.00 (9.50–47.50) months for females, revealing a gender difference (p = 0.009). Similar advantages in median (IQR) ΔFS [male: female, 0.55 (0.24–0.94) vs 0.19 (0.06–0.90), p = 0.041] and mean (95% CI) survival [57.4 (38.90–75.90) months vs 125.6 (99.80–151.50) months, p = 0.006] were also observed in females, both of which existed in sporadic ALS only when stratified by familiar or sporadic ALS.ConclusionsThe results highlight a distinct mutational distribution and natural history spectrum in ALS patients carrying SOD1 mutations in China. A prominent mild disease progression was observed in female patients, which had rarely been reported in the previous literature. This finding, together with the detailed analysis of natural history among each mutation, can have important implications for future genetic counselling and SOD1-targeted clinical trials.

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Section: Introductionmentioning

confidence: 99%

Better survival in female SOD1-mutant patients with ALS: a study of SOD1-related natural history

Tang

Liu

et al. 2019

Transl Neurodegener

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“…Moreover, the level of sulfenic acid-modified wild-type SOD1 in CSF could be determined in living ALS patients. A few biomarkers for ALS, such as phosphorylated neurofilament heavy chain and TDP-43 in CSF, have been reported 52 – 54 , 57 – 59 . Our findings suggest that the quantification of sulfenic acid-modified SOD1 in CSF could have potential value as a diagnostic laboratory tool for sporadic ALS patients, and suggest a role of sulfenic acid-modified wild-type SOD1 as a diagnostic biomarker in sporadic ALS.…”

Section: Discussionmentioning

confidence: 99%

Pathological hydrogen peroxide triggers the fibrillization of wild-type SOD1 via sulfenic acid modification of Cys-111

Liang

et al. 2018

Cell Death Dis

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Amyotrophic lateral sclerosis (ALS) involves the abnormal posttranslational modifications and fibrillization of copper, zinc superoxide dismutase (SOD1) and TDP-43. However, how SOD1-catalyzed reaction product hydrogen peroxide affects amyloid formation of SOD1 and TDP-43 remains elusory. 90% of ALS cases are sporadic and the remaining cases are familial ALS. In this paper, we demonstrate that H2O2 at pathological concentrations triggers the fibrillization of wild-type SOD1 both in vitro and in SH-SY5Y cells. Using an anti-dimedone antibody that detects sulfenic acid modification of proteins, we found that Cys-111 in wild-type SOD1 is oxidized to C-SOH by pathological concentration of H2O2, followed by the formation of sulfenic acid modified SOD1 oligomers. Furthermore, we show that such SOD1 oligomers propagate in a prion-like manner, and not only drive wild-type SOD1 to form fibrils in the cytoplasm but also induce cytoplasm mislocalization and the subsequent fibrillization of wild-type TDP-43, thereby inducing apoptosis of living cells. Thus, we propose that H2O2 at pathological concentrations triggers the fibrillization of wild-type SOD1 and subsequently induces SOD1 toxicity and TDP-43 toxicity in neuronal cells via sulfenic acid modification of Cys-111 in SOD1. Our Western blot and ELISA data demonstrate that sulfenic acid modified wild-type SOD1 level in cerebrospinal fluid of 15 sporadic ALS patients is significantly increased compared with 6 age-matched control patients. These findings can explain how H2O2 at pathologic concentrations regulates the misfolding and toxicity of SOD1 and TDP-43 associated with ALS, and suggest that sulfenic acid modification of wild-type SOD1 should play pivotal roles in the pathogenesis of sporadic ALS.

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“…Therefore, not all types of misfolded-SOD1 antibodies could detect pathological forms of wild-type SOD1 in CSF, but our study has suggested that wildtype SOD1 in CSF adopts a misfolded, toxic conformation(s) in pathological conditions of ALS and also a subset of PD and PSP. In that sense, it is important to note that levels of SOD1 in CSF of SOD1-ALS patients were reduced by oral medication with pyrimethamine [100].…”

Section: Misfolded Forms Of Sod1 In Cerebrospinal Fluid Of Alsmentioning

confidence: 99%

Does wild-type Cu/Zn-superoxide dismutase have pathogenic roles in amyotrophic lateral sclerosis?

Furukawa

Tokuda

2020

Transl Neurodegener

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Amyotrophic lateral sclerosis (ALS) is characterized by adult-onset progressive degeneration of upper and lower motor neurons. Increasing numbers of genes are found to be associated with ALS; among those, the first identified gene, SOD1 coding a Cu/Zn-superoxide dismutase protein (SOD1), has been regarded as the gold standard in the research on a pathomechanism of ALS. Abnormal accumulation of misfolded SOD1 in affected spinal motor neurons has been established as a pathological hallmark of ALS caused by mutations in SOD1 (SOD1-ALS). Nonetheless, involvement of wild-type SOD1 remains quite controversial in the pathology of ALS with no SOD1 mutations (non-SOD1 ALS), which occupies more than 90% of total ALS cases. In vitro studies have revealed post-translationally controlled misfolding and aggregation of wild-type as well as of mutant SOD1 proteins; therefore, SOD1 proteins could be a therapeutic target not only in SOD1-ALS but also in more prevailing cases, non-SOD1 ALS. In order to search for evidence on misfolding and aggregation of wild-type SOD1 in vivo, we reviewed pathological studies using mouse models and patients and then summarized arguments for and against possible involvement of wild-type SOD1 in non-SOD1 ALS as well as in SOD1-ALS.

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Pyrimethamine significantly lowers cerebrospinal fluid Cu/Zn superoxide dismutase in amyotrophic lateral sclerosis patients with SOD1 mutations

Cited by 39 publications

References 34 publications

Better survival in female SOD1-mutant patients with ALS: a study of SOD1-related natural history

Better survival in female SOD1-mutant patients with ALS: a study of SOD1-related natural history

Pathological hydrogen peroxide triggers the fibrillization of wild-type SOD1 via sulfenic acid modification of Cys-111

Does wild-type Cu/Zn-superoxide dismutase have pathogenic roles in amyotrophic lateral sclerosis?

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