title: Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons.
abstract: Parkinson's disease (PD) is characterised by the progressive loss of nigral dopamine neurons and the presence of synucleinopathy. Overexpression of α-synuclein in vivo using viral vectors has opened interesting possibilities to model PD-like pathology in rodents. However, the attempts made so far have failed to show a consistent behavioural phenotype and pronounced dopamine neurodegeneration. Using a more efficient adeno-associated viral (AAV) vector construct, which includes a WPRE enhancer element and uses the neuron-specific synapsin-1 promoter to drive the expression of human wild-type α-synuclein, we have now been able to achieve increased levels of α-synuclein in the transduced midbrain dopamine neurons sufficient to induce profound deficits in motor function, accompanied by reduced expression of proteins involved in dopamine neurotransmission and a time-dependent loss of nigral dopamine neurons, that develop progressively over 2-4 months after vector injection. As in human PD, nigral cell loss was preceded by degenerative changes in striatal axons and terminals, and the appearance of α-synuclein positive inclusions in dystrophic axons and dendrites, supporting the idea that α-synuclein-induced pathology hits the axons and terminals first and later progresses to involve also the cell bodies. The time-course of changes seen in the AAV-α-synuclein treated animals defines distinct stages of disease progression that matches the pre-symptomatic, early symptomatic, and advanced stages seen in PD patients. This model provides new interesting possibilities for studies of stage-specific pathologic mechanisms and identification of targets for disease-modifying therapeutic interventions linked to early or late stages of the disease.
authors.affiliation: Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, BMC A11, Lund 22184, Sweden. Mickael.Decressac@med.lu.se
authors.forename: M
authors.initials: M
authors.lastname: Decressac
authors.forename: B
authors.initials: B
authors.lastname: Mattsson
authors.forename: M
authors.initials: M
authors.lastname: Lundblad
authors.forename: P
authors.initials: P
authors.lastname: Weikop
authors.forename: A
authors.initials: A
authors.lastname: Björklund
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use; D001526:Behavioral Symptoms / Q000209:etiology / Q000235:genetics*; D002452:Cell Count; D002851:Chromatography, High Pressure Liquid; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D051959:ELAV Proteins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005822:Genetic Vectors / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007980:Levodopa / Q000494:pharmacology / Q000627:therapeutic use; D008636:Mesencephalon / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000235:genetics*; D010300:Parkinson Disease / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D051959:ELAV Proteins; D009419:Nerve Tissue Proteins; D050493:Vesicular Monoamine Transport Proteins; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; D007980:Levodopa; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine