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Peripheral administration of SOD1 aggregates does not transmit pathogenic aggregation to the CNS of SOD1 transgenic mice
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.ORCID iD: 0000-0002-3787-7629
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.ORCID iD: 0000-0003-0094-5429
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2021 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 9, no 1, article id 111Article in journal (Refereed) Published
Abstract [en]

The deposition of aggregated proteins is a common neuropathological denominator for neurodegenerative disorders. Experimental evidence suggests that disease propagation involves prion-like mechanisms that cause the spreading of template-directed aggregation of specific disease-associated proteins. In transgenic (Tg) mouse models of superoxide dismutase-1 (SOD1)-linked amyotrophic lateral sclerosis (ALS), inoculation of minute amounts of human SOD1 (hSOD1) aggregates into the spinal cord or peripheral nerves induces premature ALS-like disease and template-directed hSOD1 aggregation that spreads along the neuroaxis. This infectious nature of spreading pathogenic aggregates might have implications for the safety of laboratory and medical staff, recipients of donated blood or tissue, or possibly close relatives and caregivers. Here we investigate whether transmission of ALS-like disease is unique to the spinal cord and peripheral nerve inoculations or if hSOD1 aggregation might spread from the periphery into the central nervous system (CNS). We inoculated hSOD1 aggregate seeds into the peritoneal cavity, hindlimb skeletal muscle or spinal cord of adult Tg mice expressing mutant hSOD1. Although we used up to 8000 times higher dose—compared to the lowest dose transmitting disease in spinal cord inoculations—the peripheral inoculations did not transmit seeded aggregation to the CNS or premature ALS-like disease in hSOD1 Tg mice. Nor was any hSOD1 aggregation detected in the liver, kidney, skeletal muscle or sciatic nerve. To explore potential reasons for the lack of disease transmission, we examined the stability of hSOD1 aggregates and found them to be highly vulnerable to both proteases and detergent. Our findings suggest that exposed individuals and personnel handling samples from ALS patients are at low risk of any potential transmission of seeded hSOD1 aggregation.

Place, publisher, year, edition, pages
BioMed Central, 2021. Vol. 9, no 1, article id 111
Keywords [en]
Aggregate stability, ALS, Amyotrophic lateral sclerosis, Peripheral administration, Prion-like, Protein aggregation, SOD1, Superoxide dismutase 1
National Category
Neurology Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-185894DOI: 10.1186/s40478-021-01211-9ISI: 000665853700001PubMedID: 34158126Scopus ID: 2-s2.0-85109055645OAI: oai:DiVA.org:umu-185894DiVA, id: diva2:1579877
Funder
The Swedish Brain Foundation, 2015-0234The Swedish Brain Foundation, 2016-0303The Swedish Brain Foundation, 2018-0310The Swedish Brain Foundation, 2019-0320The Swedish Brain Foundation, 2020-0353Knut and Alice Wallenberg Foundation, 2012.0091Knut and Alice Wallenberg Foundation, 2014.0305Knut and Alice Wallenberg Foundation, 2020.0232Available from: 2021-07-12 Created: 2021-07-12 Last updated: 2021-07-12Bibliographically approved

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Keskin, IsilEkhtiari Bidhendi, ElahehMarklund, MatthewAndersen, Peter M.Brännström, ThomasMarklund, Stefan L.Nordström, Ulrika

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Keskin, IsilEkhtiari Bidhendi, ElahehMarklund, MatthewAndersen, Peter M.Brännström, ThomasMarklund, Stefan L.Nordström, Ulrika
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