Abstract
Multiple system atrophy (MSA), a progressive neurodegenerative disease characterized by autonomic dysfunction and motor impairment, is caused by the self-templated misfolding of the protein α-synuclein. With no treatment currently available, we sought to characterize the spread of α-synuclein in a transgenic mouse model of MSA prion propagation to support drug discovery programs for synucleinopathies. Brain homogenates from MSA patient samples or mouse-passaged MSA were inoculated either by standard freehand injection or stereotactically into TgM83+/- mice, which express human α-synuclein with the A53T mutation. Following disease onset, brains from the mice were tested for biologically active α-synuclein prions using a cell-based assay and examined for α-synuclein neuropathology. Inoculation studies using homogenates prepared from brain regions lacking detectable α-synuclein neuropathology transmitted neurological disease to mice. Terminal animals contained similar concentrations of α-synuclein prions; however, a time-course study where mice were terminated every five days through disease progression revealed that the kinetics of α-synuclein prion replication in the mice were variable. Stereotactic inoculation into the thalamus reduced variability in disease onset in the mice, although incubation times were consistent with standard inoculations. Using human samples with and without neuropathological lesions, we observed that α-synuclein prion formation precedes neuropathology in the brain, suggesting that disease in patients is not limited to brain regions containing neuropathological lesions.
Highlights
Protein misfolding diseases, or proteinopathies, are characterized by the misfolding of particular proteins, which often contain intrinsically disordered regions, into conformations with an increased β-sheet content
In 2015, we demonstrated that this same mechanism is responsible for the neurodegenerative disease multiple system atrophy (MSA); the disease is caused by the misfolding of the protein α-synuclein rather than prion protein (PrP)
Having shown that α-synuclein prions in MSA patient samples exhibit a number of properties consistent with PrP prions in Creutzfeldt–Jakob disease (CJD) patients, we sought to establish and define a rigorous transgenic mouse model of α-synuclein prion propagation to support ongoing drug discovery efforts for MSA therapeutics
Summary
Proteinopathies, are characterized by the misfolding of particular proteins, which often contain intrinsically disordered regions, into conformations with an increased β-sheet content. The protein develops the ability to serve as a self-template for additional protein misfolding [1] Through this mechanism, a normal protein can become pathogenic, or capable of spreading disease in the central nervous system [2]. A normal protein can become pathogenic, or capable of spreading disease in the central nervous system [2] This mechanism was first proposed for the prion protein (PrP) [3]; in diseases including Creutzfeldt–Jakob disease (CJD), bovine spongiform encephalopathy, and scrapie, cellular PrP (PrPC) misfolds into a disease-causing isoform termed PrPSc. Substantial work has subsequently shown that each of the diseases caused by PrPSc arises from the protein misfolding into a distinct conformation, or strain [4]. This groundbreaking work established the mechanism underlying a myriad of prion diseases and has more recently been shown to be true for several proteins: β-amyloid [5, 6], tau [7, 8], SOD-1 [9, 10], TDP-43 [11, 12], and αsynuclein [13, 14] misfold and self-propagate in cellular and animal models of disease
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