Oral and Intravenous Transmission of α-Synuclein Fibrils to Mice

Stephanie Lohmann1, Maria E. Bernis1, Babila J. Tachu1, Gültekin Tamgüney2

1 German Center for Neurodegenerative Diseases (DZNE), Bonn
2 Institute of Complex Systems - Structural Biochemistry (ICS-6), Forschungszentrum Jülich, Jülich

In synucleinopathies such as Parkinson’s disease misfolding of α-synuclein, normally a cellular and soluble protein, leads to the accumulation of insoluble protein aggregates and to central nervous system (CNS) disease. Pathological α-synuclein shows prion-like characteristics and therefore we wanted to investigate whether different routes of peripheral challenge with fibrillar α-synuclein could lead to neuroinvasion of the CNS.

We investigated the spreading of pathological α-synuclein after intracerebral, intraperitoneal, intravenous, or oral inoculation of TgM83+/− mice, overexpressing the A53T mutant of human α-synuclein, with α-synuclein fibrils. Animals were sacrificed after they developed clinical signs of disease. We stained brain and spinal cord tissue sections to determine the presence of pathological α-synuclein, which were confirmed by biochemistry for phosphorylated α-synuclein in tissue homogenates and with a time-resolved fluorescence resonance energy transfer (TR-FRET) assay for aggregated α-synuclein.

Clinical disease in ten out of ten animals was detected 133 ± 4 days after intracerebral and 208 ± 20 days after intravenous injection. Eight out of ten mice developed clinical signs of disease 192 ± 32 days after intraperitoneal injection. Oral challenge with 50 µg α-synuclein fibrils caused neurological disease in two out of eight mice in 220 days and 350 days, and challenge with 500 µg fibrils in four out of eight mice in 384 ± 131 days after oral challenge, respectively. The CNS of diseased mice displayed aggregates of sarkosyl-insoluble and phosphorylated α-synuclein, which 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.

Our findings indicate that α-synuclein fibrils do not only cause CNS disease after intracerebral challenge but also after intraperitoneal, intravenous, or oral challenge, suggesting a prion-like mechanism in pathogenesis.


Keywords: Parkinson’s disease, α -synuclein, aggregation