Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis

Bidhendi, Elaheh Ekhtiari; Bergh, Johan; Zetterström, Per; Forsberg, Karin; Pakkenberg, Bente; Andersen, Peter M.; Marklund, Stefan L.; Brännström, Thomas

doi:10.1007/s00401-018-1915-y

Cited by 61 publications

(69 citation statements)

References 39 publications

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“…Instead, the major proportion of hSOD1 aggregation was localized to the neuropil, or in ChAT + MNs ( Fig. 4d; Additional file 1: Figure S3a) as previously reported for the hSOD1 prion mouse model [8]. This distribution remained unaltered, independent of mAb treatment.…”

Section: Distribution Of Hsod1 G85r Pathology Is Unaltered In Treatedsupporting

confidence: 81%

“…Strain A hSOD1 aggregate seeds were prepared from a pool of spinal cords from end-stage hSOD1 G85R Tg mice as described previously [7,8]. Briefly, the protocol involved homogenization in 25 volumes of PBS containing 1% NP-40 and 0.5 M guanidinium hydrochloride using an Ultraturrax and sonication.…”

Section: Preparation Of Hsod1 Aggregate Seeds By Centrifugation Throumentioning

confidence: 99%

“…Using the BEM technique, we have identified two distinct SOD1 aggregate strains, denoted A and B, that can arise in the CNS of hSOD1 Tg ALS-model mice. 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].…”

Section: Introductionmentioning

confidence: 99%

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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

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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.

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Section: Distribution Of Hsod1 G85r Pathology Is Unaltered In Treatedsupporting

confidence: 81%

Section: Preparation Of Hsod1 Aggregate Seeds By Centrifugation Throumentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

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“…Recently, misfolded/aggregated proteins are considered to propagate between cells, which would contribute to the pathological progression in many of neurodegenerative diseases including SOD1 -ALS [ 82 – 86 ]. For example, premature motor neuron disease in transgenic mice expressing human SOD1 with G85R mutation is triggered by inoculation of detergent-resistant fractions of SOD1 from a SOD1 -ALS patient (G127Gfs*7) into the lumbar spinal cord [ 83 ]. Also, much attention has been paid on glymphatic system [ 87 ] and intramural peri-arterial drainage pathway [ 88 ], by which misfolded/aggregated proteins in interstitial fluid (ISF) of the brain and spinal cord could be drained into cerebrospinal fluid (CSF) and then cleared [ 89 ].…”

Section: Introductionmentioning

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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“…Recent findings in vivo suggest that prion-like growth and spread of SOD1 aggregation could be the primary disease mechanism of SOD1-induced ALS [ 7 , 8 , 12 , 28 ]. Disordered SOD1 species are critical substrates for both the nucleation and growth of aggregates [ 21 , 22 , 35 , 51 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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Mutations in superoxide dismutase 1 ( SOD1 ) cause amyotrophic lateral sclerosis (ALS). Disease pathogenesis is linked to destabilization, disorder and aggregation of the SOD1 protein. However, the non-genetic factors that promote disorder and the subsequent aggregation of SOD1 have not been studied. Mainly located to the reducing cytosol, mature SOD1 contains an oxidized disulfide bond that is important for its stability. Since O 2 is required for formation of the bond, we reasoned that low O 2 tension might be a risk factor for the pathological changes associated with ALS development. By combining biochemical approaches in an extensive range of genetically distinct patient-derived cell lines, we show that the disulfide bond is an Achilles heel of the SOD1 protein. Culture of patient-derived fibroblasts, astrocytes, and induced pluripotent stem cell-derived mixed motor neuron and astrocyte cultures (MNACs) under low O 2 tensions caused reductive bond cleavage and increases in disordered SOD1. The effects were greatest in cells derived from patients carrying ALS-linked mutations in SOD1 . However, significant increases also occurred in wild-type SOD1 in cultures derived from non-disease controls, and patients carrying mutations in other common ALS-linked genes. Compared to fibroblasts, MNACs showed far greater increases in SOD1 disorder and even aggregation of mutant SOD1s, in line with the vulnerability of the motor system to SOD1-mediated neurotoxicity. Our results show for the first time that O 2 tension is a principal determinant of SOD1 stability in human patient-derived cells. Furthermore, we provide a mechanism by which non-genetic risk factors for ALS, such as aging and other conditions causing reduced vascular perfusion, could promote disease initiation and progression. Electronic supplementary material The online version of this article (10.1007/s00401-019-01986-1) contains supplementary material, which is available to authorized users.

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Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis

Cited by 61 publications

References 39 publications

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

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

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

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

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