Kinetics of α-synuclein prions preceding neuropathological inclusions in multiple system atrophy
| Autor: | Smita S. Patel, Jisoo Lee, Amanda L. Woerman, Sabeen A. Kazmi, Steven H. Olson, Daniel A. Mordes, Abby Oehler, Stanley B. Prusiner |
|---|---|
| Přispěvatelé: | Bartz, Jason C |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Pathology animal diseases Neurodegenerative medicine.disease_cause Pathology and Laboratory Medicine Biochemistry Transgenic Prion Diseases Mice Zoonoses Drug Discovery Medicine and Health Sciences 2.1 Biological and endogenous factors Aetiology Biology (General) Neuropathology 0303 health sciences Mutation Brain Diseases 030302 biochemistry & molecular biology Brain Animal Models 3. Good health Infectious Diseases Experimental Organism Systems Neurology Veterinary Diseases Medical Microbiology Neurological alpha-Synuclein Female Research Article Genetically modified mouse medicine.medical_specialty Drug Research and Development Infectious Disease Control Prions QH301-705.5 Transgene Thalamus Immunology Mice Transgenic Mouse Models Biology Research and Analysis Methods Microbiology 03 medical and health sciences Atrophy Rare Diseases Model Organisms Virology mental disorders Genetics medicine Acquired Cognitive Impairment Animals Humans Point Mutation Molecular Biology 030304 developmental biology Synucleinopathies Pharmacology Point mutation Neurosciences Transmissible Spongiform Encephalopathy (TSE) Biology and Life Sciences Proteins Multiple System Atrophy RC581-607 medicine.disease Brain Disorders nervous system diseases Kinetics nervous system Anatomical Pathology Animal Studies Parasitology Dementia Veterinary Science Immunologic diseases. Allergy |
| Zdroj: | PLoS Pathogens, Vol 16, Iss 2, p e1008222 (2020) PLoS Pathogens PLoS pathogens, vol 16, iss 2 |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | 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. Author summary The underlying cause of disease in a group of rapidly progressing neurodegenerative disorders called prion diseases is the misfolding of the prion protein (PrP) into a conformation that can self-template and spread disease throughout the brain. Diseases caused by this phenomenon include Creutzfeldt–Jakob disease (CJD), chronic wasting disease, and bovine spongiform encephalopathy (“mad cow” disease). In 2015, we demonstrated that this same mechanism is responsible for the neurodegenerative disease multiple system atrophy (MSA); however, the disease is caused by the misfolding of the protein α-synuclein rather than PrP. Having shown that α-synuclein prions in MSA patient samples exhibit a number of properties consistent with PrP prions in 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. In this study, we identified optimized methods for transmitting MSA in a transgenic mouse model of α-synuclein prion spreading and defined disease pathogenesis in these mice. These results are needed to properly evaluate compounds that may prevent α-synuclein prion spreading. We also showed that in both human and mouse brain, α-synuclein prion spreading precedes the formation of neuropathological lesions traditionally used to define disease, yielding new insights into the progression of MSA. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
| Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |