title: Nasal inoculation with α-synuclein aggregates evokes rigidity, locomotor deficits and immunity to such misfolded species as well as dopamine.
abstract: Animal models of Parkinson's disease (PD) have been widely used to investigate the pathogenesis of this neurodegenerative disorder which is typically associated with the specific and largely disordered protein α-synuclein (α-syn). In the current study, the nasal vector was used to deliver α-syn aggregates to the brain. Both α-syn oligomers and its fibrils were firstly characterized using atomic force microscopy and the thioflavin T binding assay. The toxic oligomers alone (0.48 mg/kg) or their 50:50 combination with fibrils (in a total dose of 0.48 mg/kg) were then given intranasally for ten days in mice and PD-mimetic symptoms as well as humoral immunity to these species and dopamine (DA) were evaluated simultaneously. Open-field behavioral deficits indicated by rigidity and reduced locomotor activity were induced by the dual administration of α-syn oligomers plus fibrils but not the oligomers by themselves under the 10-day dosing regimen. In contrast, using ELISA, high levels of serum autoantibodies to α-syn monomeric, oligomeric and fibrillar conformers as well as DA were observed in both treatment groups reflecting immune system activation and this substantiates previous clinical studies in Parkinson's disease patients. Thus, nasal administration of α-syn amyloidogenic species may be a potential experimental PD model which results not only in motor deficits but also incitement of humoral protection to mimic the disease. Such a paradigm may be exploitable in the quest for potential therapeutic strategies and further studies are warranted.
authors: P K Anokhin Institute of Normal Physiology RAMS, Moscow, Russia.
authors: Marina A
authors: MA
authors: Gruden
authors: Tatiana V
authors: TV
authors: Davidova
authors: Kiran
authors: K
authors: Yanamandra
authors: Valery G
authors: VG
authors: Kucheryanu
authors: Ludmilla A
authors: LA
authors: Morozova-Roche
authors: Vladimir V
authors: VV
authors: Sherstnev
authors: Robert D E
authors: RD
authors: Sewell
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D004298:Dopamine / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects* / Q000276:immunology; D009127:Muscle Rigidity / Q000276:immunology; D010302:Parkinson Disease, Secondary / Q000276:immunology; D014611:Vaccination; D051844:alpha-Synuclein / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D051844:alpha-Synuclein; D004298:Dopamine