Peripheral administration of SOD1 aggregates does not transmit pathogenic aggregation to the CNS of SOD1 transgenic mice
Abstract 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 pr...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-06-01
|
| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-021-01211-9 |
| _version_ | 1819063155588857856 |
|---|---|
| author | Isil Keskin Elaheh Ekhtiari Bidhendi Matthew Marklund Peter M. Andersen Thomas Brännström Stefan L. Marklund Ulrika Nordström |
| author_facet | Isil Keskin Elaheh Ekhtiari Bidhendi Matthew Marklund Peter M. Andersen Thomas Brännström Stefan L. Marklund Ulrika Nordström |
| author_sort | Isil Keskin |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-21T15:10:11Z |
| format | Article |
| id | doaj.art-a0d601b0855a439383f85a8019dea14b |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-21T15:10:11Z |
| publishDate | 2021-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-a0d601b0855a439383f85a8019dea14b2022-12-21T18:59:19ZengBMCActa Neuropathologica Communications2051-59602021-06-019111310.1186/s40478-021-01211-9Peripheral administration of SOD1 aggregates does not transmit pathogenic aggregation to the CNS of SOD1 transgenic miceIsil Keskin0Elaheh Ekhtiari Bidhendi1Matthew Marklund2Peter M. Andersen3Thomas Brännström4Stefan L. Marklund5Ulrika Nordström6Department of Medical Biosciences, Pathology, Umeå UniversityDepartment of Clinical Sciences, Neurosciences, Umeå UniversityDepartment of Medical Biosciences, Pathology, Umeå UniversityDepartment of Clinical Sciences, Neurosciences, Umeå UniversityDepartment of Medical Biosciences, Pathology, Umeå UniversityDepartment of Medical Biosciences, Clinical Chemistry, Umeå UniversityDepartment of Clinical Sciences, Neurosciences, Umeå UniversityAbstract 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.https://doi.org/10.1186/s40478-021-01211-9Amyotrophic lateral sclerosisALSSuperoxide dismutase 1SOD1Protein aggregationPrion-like |
| spellingShingle | Isil Keskin Elaheh Ekhtiari Bidhendi Matthew Marklund Peter M. Andersen Thomas Brännström Stefan L. Marklund Ulrika Nordström Peripheral administration of SOD1 aggregates does not transmit pathogenic aggregation to the CNS of SOD1 transgenic mice Acta Neuropathologica Communications Amyotrophic lateral sclerosis ALS Superoxide dismutase 1 SOD1 Protein aggregation Prion-like |
| title | Peripheral administration of SOD1 aggregates does not transmit pathogenic aggregation to the CNS of SOD1 transgenic mice |
| title_full | Peripheral administration of SOD1 aggregates does not transmit pathogenic aggregation to the CNS of SOD1 transgenic mice |
| title_fullStr | Peripheral administration of SOD1 aggregates does not transmit pathogenic aggregation to the CNS of SOD1 transgenic mice |
| title_full_unstemmed | Peripheral administration of SOD1 aggregates does not transmit pathogenic aggregation to the CNS of SOD1 transgenic mice |
| title_short | Peripheral administration of SOD1 aggregates does not transmit pathogenic aggregation to the CNS of SOD1 transgenic mice |
| title_sort | peripheral administration of sod1 aggregates does not transmit pathogenic aggregation to the cns of sod1 transgenic mice |
| topic | Amyotrophic lateral sclerosis ALS Superoxide dismutase 1 SOD1 Protein aggregation Prion-like |
| url | https://doi.org/10.1186/s40478-021-01211-9 |
| work_keys_str_mv | AT isilkeskin peripheraladministrationofsod1aggregatesdoesnottransmitpathogenicaggregationtothecnsofsod1transgenicmice AT elahehekhtiaribidhendi peripheraladministrationofsod1aggregatesdoesnottransmitpathogenicaggregationtothecnsofsod1transgenicmice AT matthewmarklund peripheraladministrationofsod1aggregatesdoesnottransmitpathogenicaggregationtothecnsofsod1transgenicmice AT petermandersen peripheraladministrationofsod1aggregatesdoesnottransmitpathogenicaggregationtothecnsofsod1transgenicmice AT thomasbrannstrom peripheraladministrationofsod1aggregatesdoesnottransmitpathogenicaggregationtothecnsofsod1transgenicmice AT stefanlmarklund peripheraladministrationofsod1aggregatesdoesnottransmitpathogenicaggregationtothecnsofsod1transgenicmice AT ulrikanordstrom peripheraladministrationofsod1aggregatesdoesnottransmitpathogenicaggregationtothecnsofsod1transgenicmice |