Abstract
Parkinson’s disease and related disorders are neuropathologically characterized by cellular deposits of misfolded and aggregated α-synuclein in the CNS. Disease-associated α-synuclein adopts a conformation that causes it to form oligomers and fibrils, which have reduced solubility, become hyperphosphorylated, and contribute to the spatiotemporal spreading of pathology in the CNS. The infectious properties of disease-associated α-synuclein, e.g., by which peripheral route and with which efficiency it can be transmitted, are not fully understood. Here, we investigated the potential of α-synuclein fibrils to induce neurological disease in TgM83+/− mice expressing the A53T mutant of human α-synuclein after oral or intravenous challenge and compared it to intraperitoneal and intracerebral challenge. Oral challenge with 50 µg of α-synuclein fibrils caused neurological disease in two out of eight mice in 220 days and 350 days, and challenge with 500 µg in four out of eight mice in 384 ± 131 days, respectively. Intravenous challenge with 50 µg of α-synuclein fibrils led to disease in 208 ± 20 days in 10 out of 10 mice and was in duration comparable to intraperitoneal challenge with 50 µg of α-synuclein fibrils, which caused disease in 10 out of 10 mice in 202 ± 35 days. Ten out of 10 mice that were each intracerebrally challenged with 10 µg or 50 µg of α-synuclein fibrils developed disease in 156 ± 20 days and 133 ± 4 days, respectively. The CNS of diseased mice displayed aggregates of sarkosyl-insoluble and phosphorylated α-synuclein, which colocalized with ubiquitin and p62 and were accompanied by gliosis indicative of neuroinflammation. In contrast, none of the control mice that were challenged with bovine serum albumin via the same routes developed any neurological disease or neuropathology. These findings are important, because they show that α-synuclein fibrils can neuroinvade the CNS after a single oral or intravenous challenge and cause neuropathology and disease.
Highlights
Introduction αSynuclein is a soluble, cytosolic protein with a yet not fully identified function and the ability to adopt one or more pathological conformations that have been identified in cellular inclusions in a group of neurodegenerative conditions designated as synucleinopathies [11, 50, 51, 59]
Two additional mice died after oral challenge with α-synuclein fibrils in the low-dose group at 264 days and 355 days and two in the high-dose group at 150 days and 192 days without showing signs of neurological disease and without us being able to analyze them for neuropathology
Our data demonstrate that a single oral or intravenous challenge with α-synuclein fibrils can induce neurological disease in TgM83+/− mice, as we have previously shown for intraglossal and intraperitoneal challenge [10]
Summary
Introduction αSynuclein is a soluble, cytosolic protein with a yet not fully identified function and the ability to adopt one or more pathological conformations that have been identified in cellular inclusions in a group of neurodegenerative conditions designated as synucleinopathies [11, 50, 51, 59]. Because prions can be transmitted orally or by blood, for instance, bovine spongiform encephalopathy (BSE) prions have been transmitted from infected cattle to humans by the consumption of tainted beef products, and the resulting variant Creutzfeldt–Jakob disease (CJD) prions between humans by blood transfusion, we wondered whether α-synuclein prions could be transmitted via these two routes as well [20, 21] To address this question, we challenged TgM83+/− mice expressing the A53T mutant of human α-synuclein with recombinant fibrils of human, wild-type α-synuclein, or bovine serum albumin (BSA) as a negative control by the oral and intravenous route [17]. Our results unmistakably show that a single challenge with α-synuclein fibrils by the oral, intravenous, or intraperitoneal route can be sufficient for α-synuclein fibrils to invade the CNS and to cause neuropathology and disease in TgM83+/− mice
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