The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension

Keskin, Isil; Forsgren, Elin; Lehmann, Manuela; Andersen, Peter M.; Brännström, Thomas; Lange, Dale J.; Synofzik, Matthis; Nordström, Ulrika; Zetterström, Per; Marklund, Stefan L.; Gilthorpe, Jonathan

doi:10.1101/320283

Cited by 8 publications

(8 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sympathetic excitability enhancement may also play a role in the pathway of SBP to ALS, which increases SBP and aggravates oxygen consumption in ALS. Relatively low oxygen tension promotes the cleavage of reductive bonds in the SOD1 protein and increases the disordered and aggregated SOD1 protein, which intensi es ALS pathological spread [32]. Recently, some sympathetic dysfunctional symptoms have been reported in ALS patients, including decreased heart rate variability, cardiac sympathetic nerve degeneration [33,34], and decreased norepinephrine levels [35].…”

Section: Discussionmentioning

confidence: 99%

Assessing the role of blood pressure in amyotrophic lateral sclerosis: a Mendelian randomization study

Xia

Zhang

et al. 2021

Preprint

View full text Add to dashboard Cite

Background Observational studies have suggested a close but controversial relationship between blood pressure (BP) and amyotrophic lateral sclerosis (ALS). However, it remains unclear whether this association is causal. The authors employed a bidirectional two-sample Mendelian randomization (MR) approach to investigate whether there is a causal relationship between BP and ALS. Genetic proxies for systolic blood pressure (SBP), diastolic blood pressure (DBP), antihypertension drugs (AHDs), ALS, and their corresponding genome-wide association studies (GWAS) summary datasets were obtained from the updated largest studies. Inverse variance weighted (IVW) method was adopted as the main approach to examine the effect of BP on ALS and four other MR methods for sensitivity analyses. To exclude the interference between SBP and DBP, multivariable MR was used. Results We found that genetically determined increased DBP was a protective factor for ALS (OR = 0.978, 95% CI 0.960–0.996, P = 0.017), and increased SBP was an independent risk factor for ALS (OR = 1.014, 95% CI 1.003–1.025, P = 0.015). The high level of targeted protein of Calcium channel blocker (CCB) showed a causative relationship with ALS (OR = 0.985, 95% CI 0.971-1.000, P = 0.049). No evidence was revealed that ALS caused results change of BP measurements. Conclusions This study demonstrated that an increase in DBP is a protective factor for ALS, and increased SBP is independently risk for ALS, which may be related to sympathetic excitability. Blood pressure management is important in ALS, in which CCB may be a promising candidate.

show abstract

Section: Discussionmentioning

confidence: 99%

Assessing the role of blood pressure in amyotrophic lateral sclerosis: a Mendelian randomization study

Xia

Zhang

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…A caveat to the approach of promoting dimer stability for SOD1associated ALS mutants is that SOD1 dimer formation primarily occurs when monomers are already metal replete and disulfide oxidized: a species of SOD1 which is still highly stable even when containing ALS-associated mutations [72]. Evidence points towards immature metal depleted SOD1 being a precursor to the toxic forms of misfolded or aggregated SOD1 [4,10,18,19] and, until recently, effective pharmacological chaperones targeting immature SOD1 were elusive. Ebselen is considered to have a potential dual effect on SOD1 maturation, facilitating disulfide formation, and increasing dimer affinity through binding at Cys111 [30], although it should be noted that in vivo, ebselen binding at Cys111 is unlikely due to the presence of reduced glutathione within cells.…”

Section: Discussionmentioning

confidence: 99%

“…Metal-binding region (MBR) mutants affect copper or zinc coordination and activity while wild-type-like (WTL) mutants retain high levels of enzymatic activity when mature [16,17]. Immature SOD1, lacking PTMs, is prone to misfolding and is the central component of intracellular aggregates found with ALS neuronal tissues [3,8,10,11,[18][19][20], whereas mature SOD1 is highly stable [21]. Maturation and misfolding are therefore antagonistic pathways that dictate SOD1 toxicity.…”

Section: Introductionmentioning

confidence: 99%

A copper chaperone–mimetic polytherapy for SOD1-associated amyotrophic lateral sclerosis

McAlary

Shephard

Wright

et al. 2022

Journal of Biological Chemistry

View full text Add to dashboard Cite

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

show abstract

“…Moreover, strain A or B aggregate seeds, prepared from Tg mouse or ALS patients spinal cord post mortem, transmit template-directed aggregation and induce premature fatal paralysis when inoculated into spinal cord of pre-symptomatic adult hSOD1 Tg mice [ 7 , 8 ]. A number of other studies have provided additional evidence for a prion-like spread of hSOD1 aggregation in cell culture [ 5 , 16 , 17 , 22 , 27 , 30 ], and in mouse models [ 2 , 3 , 5 , 12 , 16 , 17 , 27 , 31 , 32 ]. Together, these findings suggest that transmission of aggregation may be a key mechanism for the progressive spread of clinical signs and symptoms observed in ALS patients.…”

Section: Introductionmentioning

confidence: 99%

Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice

Lehmann

Marklund

Bolender

et al. 2020

acta neuropathol commun

Self Cite

View full text Add to dashboard Cite

Increasing evidence suggests that propagation of the motor neuron disease amyotrophic lateral sclerosis (ALS) involves the pathogenic aggregation of disease-associated proteins that spread in a prion-like manner. We have identified two aggregate strains of human superoxide dismutase 1 (hSOD1) that arise in the CNS of transgenic mouse models of SOD1-mediated ALS. Both strains transmit template-directed aggregation and premature fatal paralysis when inoculated into the spinal cord of adult hSOD1 transgenic mice. This spread of pathogenic aggregation could be a potential target for immunotherapeutic intervention. Here we generated mouse monoclonal antibodies (mAbs) directed to exposed epitopes in hSOD1 aggregate strains and identified an aggregate selective mAb that targets the aa 143–153 C-terminal extremity of hSOD1 (αSOD1143–153). Both pre-incubation of seeds with αSOD1143–153 prior to inoculation, and weekly intraperitoneal (i.p.) administration attenuated transmission of pathogenic aggregation and prolonged the survival of seed-inoculated hSOD1G85R Tg mice. In contrast, administration of a mAb targeting aa 65–72 (αSOD165–72), which exhibits high affinity towards monomeric disordered hSOD1, had an adverse effect and aggravated seed induced premature ALS-like disease. Although the mAbs reached similar concentrations in CSF, only αSOD1143–153 was found in association with aggregated hSOD1 in spinal cord homogenates. Our results suggest that an aggregate-selective immunotherapeutic approach may suppress seeded transmission of pathogenic aggregation in ALS. However, long-term administration of αSOD1143–153 was unable to prolong the lifespan of non-inoculated hSOD1G85R Tg mice. Thus, spontaneously initiated hSOD1 aggregation in spinal motor neurons may be poorly accessible to therapeutic antibodies.

show abstract

The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension

Cited by 8 publications

References 70 publications

Assessing the role of blood pressure in amyotrophic lateral sclerosis: a Mendelian randomization study

Assessing the role of blood pressure in amyotrophic lateral sclerosis: a Mendelian randomization study

A copper chaperone–mimetic polytherapy for SOD1-associated amyotrophic lateral sclerosis

Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice

Contact Info

Product

Resources

About