Journal
ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume 9, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s40478-021-01211-9
Keywords
Amyotrophic lateral sclerosis; ALS; Superoxide dismutase 1; SOD1; Protein aggregation; Prion-like; Peripheral administration; Aggregate stability
Categories
Funding
- Umea University
- Swedish Research Council [VR-MH 2012-3167, 2015-02804, 2017-03100, 2019-01707]
- Knut and Alice Wallenberg Foundation [2012.0091, 2014.0305, 2020.0232]
- Swedish Brain Foundation (Hjarnfonden) [2015-0234, 2016-0303, 2018-0310, 2019-0320, 2020-0353]
- Ulla-Carin Lindquist Foundation
- Bertil Hallsten Foundation
- Torsten and Ragnar Soderberg Foundation
- Neuroforbundet
- Vasterbotten County Council
- King Gustaf V and Queen Victoria's Freemason's Foundation
- Kempe Foundations, Sweden
- Research Foundation at the Medical Faculty of Umea University, Sweden
- Research Foundation for Neurosciences at Umea University, Sweden
- Swedish Research Council [2015-02804, 2019-01707, 2017-03100] Funding Source: Swedish Research Council
- Vinnova [2019-01707] Funding Source: Vinnova
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The deposition of aggregated proteins is a common feature in neurodegenerative disorders. Experimental evidence suggests that disease propagation involves prion-like mechanisms, causing the spreading of specific disease-associated proteins. In mouse models, inoculation of minute amounts of human SOD1 aggregates into the spinal cord or peripheral nerves can induce premature ALS-like disease, but higher doses given through different routes did not lead to disease transmission.
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.
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