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Single injection of small-molecule amyloid accelerator results in cell death of nigral dopamine neurons in mice

The assembly process of α-synuclein toward amyloid fibers is linked to neurodegeneration in Parkinson’s disease. In the present study, we capitalized on the in vitro discovery of a small-molecule accelerator of α-synuclein amyloid formation and assessed its effects when injected in brains of normal...

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Detalles Bibliográficos
Autores principales: Chermenina, Maria, Chorell, Erik, Pokrzywa, Małgorzata, Antti, Henrik, Almqvist, Fredrik, Strömberg, Ingrid, Wittung-Stafshede, Pernilla
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516562/
https://www.ncbi.nlm.nih.gov/pubmed/28725689
http://dx.doi.org/10.1038/npjparkd.2015.24
Descripción
Sumario:The assembly process of α-synuclein toward amyloid fibers is linked to neurodegeneration in Parkinson’s disease. In the present study, we capitalized on the in vitro discovery of a small-molecule accelerator of α-synuclein amyloid formation and assessed its effects when injected in brains of normal mice. An accelerator and an inhibitor of α-synuclein amyloid formation, as well as vehicle only, were injected into the striatum of normal mice and followed by behavioral evaluation, immunohistochemistry, and metabolomics up to six months later. The effects of molecules injected into the substantia nigra of normal and α-synuclein knock-out mice were also analyzed. When accelerator or inhibitor was injected into the brain of normal mice no acute compound toxicity was found. However, 6 months after single striatal injection of accelerator, mice sensorimotor functions were impaired, whereas mice injected with inhibitor had no dysfunctions. Injection of accelerator (but not inhibitor or vehicle) into the substantia nigra revealed significant loss of tyrosine hydroxylase (TH)-positive neurons after 3 months. No loss of TH-positive neurons was found in α-synuclein knock-out mice injected with accelerator into the substantia nigra. Metabolic serum profiles from accelerator-injected normal mice matched those of newly diagnosed Parkinson’s disease patients, whereas the profiles from inhibitor-injected normal mice matched controls. Single inoculation of a small-molecule amyloid accelerator may be a new approach for studies of early events during dopamine neurodegeneration in mice.