title: Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice.
abstract: Parkinson's disease is characterized by abundant α-synuclein (α-Syn) neuronal inclusions, known as Lewy bodies and Lewy neurites, and the massive loss of midbrain dopamine neurons. However, a cause-and-effect relationship between Lewy inclusion formation and neurodegeneration remains unclear. Here, we found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic α-Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn and Parkinson's-like Lewy pathology in anatomically interconnected regions. Lewy pathology accumulation resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta, but not in the adjacent ventral tegmental area, and was accompanied by reduced dopamine levels culminating in motor deficits. This recapitulation of a neurodegenerative cascade thus establishes a mechanistic link between transmission of pathologic α-Syn and the cardinal features of Parkinson's disease.
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-4283, USA.
authors.forename: Kelvin C
authors.initials: KC
authors.lastname: Luk
authors.forename: Victoria
authors.initials: V
authors.lastname: Kehm
authors.forename: Jenna
authors.initials: J
authors.lastname: Carroll
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Patrick
authors.initials: P
authors.lastname: O'Brien
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004298:Dopamine; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007267:Injections; D016631:Lewy Bodies / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology; D017510:Protein Folding; D021381:Protein Transport; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; D051844:alpha-Synuclein; D004298:Dopamine