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.
Highlights
Amyotrophic lateral sclerosis (ALS) is characterized by adult-onset progressive degeneration of upper and lower motor neurons
We previously showed that inoculation of two distinct strains of human superoxide dismutase-1 (SOD1) (hSOD1) aggregate seeds, prepared from the spinal cords from terminally ill Tg ALS-model mice into the spinal cords of asymptomatic Tg mice expressing mutant hSOD1, induced spreading of template-directed hSOD1 aggregation and premature fatal ALS-like disease [10, 11]
We found no evidence for transmission of hSOD1 (See figure on page.) Fig. 2 Intraperitoneal administration of hSOD1 aggregate seeds does not induce hSOD1 aggregation in the central nervous system (CNS) or peripheral tissues. a and b Plots depict hSOD1 aggregates detected in the CNS and peripheral organs of hSOD1G85R Tg mice that were inoculated with hSOD1G85R Tg or control spinal cord homogenates into the peritoneal cavity
Summary
Amyotrophic lateral sclerosis (ALS) is characterized by adult-onset progressive degeneration of upper and lower motor neurons. We previously showed that inoculation of two distinct strains (type A and B) of hSOD1 aggregate seeds, prepared from the spinal cords from terminally ill Tg ALS-model mice into the spinal cords of asymptomatic Tg mice expressing mutant hSOD1, induced spreading of template-directed hSOD1 aggregation and premature fatal ALS-like disease [10, 11]. Inoculation of ALS patient-derived hSOD1 aggregate seeds into the spinal cord induced spreading aggregation, and an aggressive premature motor neuron disease in hSOD1 Tg mice [23]. Ayers et al found that both spinal cord and sciatic nerve inoculations, using homogenates from spinal cords of terminally ill hSOD1 Tg mice, transmit ALS-like disease in mice expressing hSOD1 fused to yellow fluorescent protein [5, 6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
