title: Transmission of Soluble and Insoluble α-Synuclein to Mice.
abstract: The neurodegenerative synucleinopathies, which include Parkinson disease, multiple-system atrophy, and Lewy body disease, are characterized by the presence of abundant neuronal inclusions called Lewy bodies and Lewy neurites. These disorders remain incurable, and a greater understanding of the pathologic processes is needed for effective treatment strategies to be developed. Recent data suggest that pathogenic misfolding of the presynaptic protein, α-synuclein (α-syn), and subsequent aggregation and accumulation are fundamental to the disease process. It is hypothesized that the misfolded isoform is able to induce misfolding of normal endogenous α-syn, much like what occurs in the prion diseases. Recent work highlighting the seeding effect of pathogenic α-syn has largely focused on the detergent-insoluble species of the protein. In this study, we performed intracerebral inoculations of the sarkosyl-insoluble or sarkosyl-soluble fractions of human Lewy body disease brain homogenate and show that both fractions induce CNS pathology in mice at 4 months after injection. Disease-associated deposits accumulated both near and distal to the site of the injection, suggesting a cell-to-cell spread via recruitment of α-syn. These results provide further insight into the prion-like mechanisms of α-syn and suggest that disease-associated α-syn is not homogeneous within a single patient but might exist in both soluble and insoluble isoforms.
authors.affiliation: From the Department of Neuroscience (DRJ, MD, ATB, MD, MEM, DWD, PJM) and Mayo Graduate School (PJM), Mayo Clinic, Jacksonville, Florida.
authors.forename: Daryl Rhys
authors.initials: DR
authors.lastname: Jones
authors.forename: Marion
authors.initials: M
authors.lastname: Delenclos
authors.forename: AnnMarie T
authors.initials: AT
authors.lastname: Baine
authors.forename: Michael
authors.initials: M
authors.lastname: DeTure
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Murray
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: McLean
mesh_terms: D000221:Adaptation, Ocular / Q000235:genetics; D000367:Age Factors; D000368:Aged; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D020961:Lewy Body Disease / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D008854:Microscopy, Electron; D053580:Muscle Strength / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D012521:Sarcosine / Q000031:analogs & derivatives / Q000494:pharmacology; D051844:alpha-Synuclein / Q000008:administration & dosage / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D003902:Detergents; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D010982:Platelet-Derived Growth Factor; D051844:alpha-Synuclein; C025231:sarkosyl; D012521:Sarcosine