title: Progressive neurodegeneration or endogenous compensation in an animal model of Parkinson's disease produced by decreasing doses of alpha-synuclein.
abstract: The pathological hallmarks of Parkinson's disease (PD) are degeneration of dopamine (DA) neurons of the substantia nigra (SN) and the presence of alpha-synuclein (α-syn)-rich Lewy bodies in DA cells that remain. To model these aspects of the disease, we previously showed that high titer (5.1×10exp12 gp/ml) AAV1/2 driven expression of A53T α-syn in the SN of rats caused nigrostriatal pathology including a loss of DA neurons, but also with toxicity in the GFP control group. In the current study, we evaluate the effects of two lower titers by dilution of the vector (1∶3 [1.7×10exp12] and 1∶10 [5.1×10exp11]) to define a concentration that produced pathology specific for α-syn. In GFP and empty vector groups there were no behavioural or post-mortem changes at 3 or 6 weeks post-administration at either vector dose. Dilution of the AAV1/2 A53T α-syn (1:3) produced significant paw use asymmetry, reductions in striatal tyrosine hydroxylase (TH), and increases in DA turnover at 3 weeks in the absence of overt pathology. By 6 weeks greater evidence of pathology was observed and included, reductions in SN DA neurons, striatal DA, TH and DA-transporter, along with a sustained behavioural deficit. In contrast, the 1:10 AAV1/2 A53T α-syn treated animals showed normalization between 3 and 6 weeks in paw use asymmetry, reductions in striatal TH, and increased DA turnover. Progression of dopaminergic deficits using the 1:3 titer of AAV1/2 A53Tα-syn provides a platform for evaluating treatments directed at preventing and/or reversing synucleinopathy. Use of the 1:10 titer of AAV1/2 A53T α-syn provides an opportunity to study mechanisms of endogenous compensation. Furthermore, these data highlight the need to characterize the titer of vector being utilized, when using AAV to express pathogenic proteins and model disease process, to avoid producing non-specific effects.
authors.affiliation: Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada. jkoprich@uhnres.utoronto.ca
authors.forename: James B
authors.initials: JB
authors.lastname: Koprich
authors.forename: Tom H
authors.initials: TH
authors.lastname: Johnston
authors.forename: Philippe
authors.initials: P
authors.lastname: Huot
authors.forename: M Gabriela
authors.initials: MG
authors.lastname: Reyes
authors.forename: Maria
authors.initials: M
authors.lastname: Espinosa
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Brotchie
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D002452:Cell Count; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005260:Female; D005552:Forelimb; D015316:Genetic Therapy; D005822:Genetic Vectors; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000473:pathology*; D010300:Parkinson Disease / Q000473:pathology / Q000628:therapy*; D016548:Prosencephalon / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000201:enzymology / Q000473:pathology; D019076:Transgenes / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics* / Q000627:therapeutic use*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase