Peripheral Challenge with Alpha-Synuclein Fibrils Results in Parkinson's Disease-like Signs in Mice

Date/Time: 17 October 2018, 12:00 PM
Speaker: Dr. Gultekin Tamguney
Speaker Affiliation: Research Group Leader, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Venue: John A. Burns School of Medicine, Medical Education Building Auditorium (Room 315)

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Description: Alpha-synuclein is a soluble cytoplasmic protein that in some neurodegenerative diseases forms pathological deposits, such as Lewy bodies and Lewy neurites in neurons of patients with Parkinson’s disease. After intracerebral inoculation in transgenic and wild-type mice, pathological alpha-synuclein propagates in a prion-like manner causing neurodegeneration. We investigated the ability of misfolded alpha-synuclein to neuroinvade the CNS and induce disease after peripheral inoculation. For inoculation experiments we used Tg(M83+/-Gfap -luc+/-) mice hemizygously expressing luciferase and human alpha-synuclein with the familial A53T mutation. Mice challenged with phosphate-buffered saline or bovine serum albumin remained healthy, whereas intraperitoneal, intravenous, and oral challenge with alpha-synuclein fibrils lead to CNS disease with signs of kyphosis and paralysis. Biochemical analysis showed that sick mice had accumulated aggregates of sarkosyl-insoluble and phosphorylated a-synuclein in their brains and spinal cords. Neuropathological analysis revealed that CNS deposits of misfolded alpha-synuclein colocalized with ubiquitin and p62. Neurologic illness was accompanied by neuroinflammation, which was confirmed by immunofluorescence staining for GFAP and IBA-1 and by bioluminescence imaging. We show that peripheral challenge with alpha-synuclein fibrils induces neurodegeneration in Tg(M83+/-Gfap -luc+/-) mice.
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