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

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Ekhtiari Bidhendi, E, Bergh, J, Zetterström, P, Forsberg, K, Pakkenberg, B, Andersen, PM, Marklund, SL & Brännström, T 2018, 'Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis' Acta Neuropathologica. https://doi.org/10.1007/s00401-018-1915-y

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Ekhtiari Bidhendi, Elaheh ; Bergh, Johan ; Zetterström, Per ; Forsberg, Karin ; Pakkenberg, Bente ; Andersen, Peter M ; Marklund, Stefan L ; Brännström, Thomas. / Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis. I: Acta Neuropathologica. 2018.

Bibtex

@article{28f9714edf0a48c280a4745ec3cfb3ef,
title = "Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis",
abstract = "Motor neurons containing aggregates of superoxide dismutase 1 (SOD1) are hallmarks of amyotrophic lateral sclerosis (ALS) caused by mutations in the gene encoding SOD1. We have previously reported that two strains of mutant human (h) SOD1 aggregates (denoted A and B) can arise in hSOD1-transgenic models for ALS and that inoculation of such aggregates into the lumbar spinal cord of mice results in rostrally spreading, templated hSOD1 aggregation and premature fatal ALS-like disease. Here, we explored whether mutant hSOD1 aggregates with prion-like properties also exist in human ALS. Aggregate seeds were prepared from spinal cords from an ALS patient carrying the hSOD1G127Gfs*7 truncation mutation and from mice transgenic for the same mutation. To separate from mono-, di- or any oligomeric hSOD1 species, the seed preparation protocol included ultracentrifugation through a density cushion. The core structure of hSOD1G127Gfs*7 aggregates present in mice was strain A-like. Inoculation of the patient- or mouse-derived seeds into lumbar spinal cord of adult hSOD1-expressing mice induced strain A aggregation propagating along the neuraxis and premature fatal ALS-like disease (p < 0.0001). Inoculation of human or murine control seeds had no effect. The potencies of the ALS patient-derived seed preparations were high and disease was initiated in the transgenic mice by levels of hSOD1G127Gfs*7 aggregates much lower than those found in the motor system of patients carrying the mutation. The results suggest that prion-like growth and spread of hSOD1 aggregation could be the primary pathogenic mechanism, not only in hSOD1 transgenic rodent models, but also in human ALS.",
author = "{Ekhtiari Bidhendi}, Elaheh and Johan Bergh and Per Zetterstr{\"o}m and Karin Forsberg and Bente Pakkenberg and Andersen, {Peter M} and Marklund, {Stefan L} and Thomas Br{\"a}nnstr{\"o}m",
year = "2018",
month = "10",
day = "3",
doi = "10.1007/s00401-018-1915-y",
language = "English",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer",

}

RIS

TY - JOUR

T1 - Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis

AU - Ekhtiari Bidhendi, Elaheh

AU - Bergh, Johan

AU - Zetterström, Per

AU - Forsberg, Karin

AU - Pakkenberg, Bente

AU - Andersen, Peter M

AU - Marklund, Stefan L

AU - Brännström, Thomas

PY - 2018/10/3

Y1 - 2018/10/3

N2 - Motor neurons containing aggregates of superoxide dismutase 1 (SOD1) are hallmarks of amyotrophic lateral sclerosis (ALS) caused by mutations in the gene encoding SOD1. We have previously reported that two strains of mutant human (h) SOD1 aggregates (denoted A and B) can arise in hSOD1-transgenic models for ALS and that inoculation of such aggregates into the lumbar spinal cord of mice results in rostrally spreading, templated hSOD1 aggregation and premature fatal ALS-like disease. Here, we explored whether mutant hSOD1 aggregates with prion-like properties also exist in human ALS. Aggregate seeds were prepared from spinal cords from an ALS patient carrying the hSOD1G127Gfs*7 truncation mutation and from mice transgenic for the same mutation. To separate from mono-, di- or any oligomeric hSOD1 species, the seed preparation protocol included ultracentrifugation through a density cushion. The core structure of hSOD1G127Gfs*7 aggregates present in mice was strain A-like. Inoculation of the patient- or mouse-derived seeds into lumbar spinal cord of adult hSOD1-expressing mice induced strain A aggregation propagating along the neuraxis and premature fatal ALS-like disease (p < 0.0001). Inoculation of human or murine control seeds had no effect. The potencies of the ALS patient-derived seed preparations were high and disease was initiated in the transgenic mice by levels of hSOD1G127Gfs*7 aggregates much lower than those found in the motor system of patients carrying the mutation. The results suggest that prion-like growth and spread of hSOD1 aggregation could be the primary pathogenic mechanism, not only in hSOD1 transgenic rodent models, but also in human ALS.

AB - Motor neurons containing aggregates of superoxide dismutase 1 (SOD1) are hallmarks of amyotrophic lateral sclerosis (ALS) caused by mutations in the gene encoding SOD1. We have previously reported that two strains of mutant human (h) SOD1 aggregates (denoted A and B) can arise in hSOD1-transgenic models for ALS and that inoculation of such aggregates into the lumbar spinal cord of mice results in rostrally spreading, templated hSOD1 aggregation and premature fatal ALS-like disease. Here, we explored whether mutant hSOD1 aggregates with prion-like properties also exist in human ALS. Aggregate seeds were prepared from spinal cords from an ALS patient carrying the hSOD1G127Gfs*7 truncation mutation and from mice transgenic for the same mutation. To separate from mono-, di- or any oligomeric hSOD1 species, the seed preparation protocol included ultracentrifugation through a density cushion. The core structure of hSOD1G127Gfs*7 aggregates present in mice was strain A-like. Inoculation of the patient- or mouse-derived seeds into lumbar spinal cord of adult hSOD1-expressing mice induced strain A aggregation propagating along the neuraxis and premature fatal ALS-like disease (p < 0.0001). Inoculation of human or murine control seeds had no effect. The potencies of the ALS patient-derived seed preparations were high and disease was initiated in the transgenic mice by levels of hSOD1G127Gfs*7 aggregates much lower than those found in the motor system of patients carrying the mutation. The results suggest that prion-like growth and spread of hSOD1 aggregation could be the primary pathogenic mechanism, not only in hSOD1 transgenic rodent models, but also in human ALS.

U2 - 10.1007/s00401-018-1915-y

DO - 10.1007/s00401-018-1915-y

M3 - Journal article

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

ER -

ID: 55663791