Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons

Neurobiol Dis. 2012 Mar;45(3):939-53. doi: 10.1016/j.nbd.2011.12.013. Epub 2011 Dec 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamine / pharmacology
  • Analysis of Variance
  • Animals
  • Antiparkinson Agents / pharmacology
  • Antiparkinson Agents / therapeutic use
  • Behavioral Symptoms / etiology
  • Behavioral Symptoms / genetics*
  • Cell Count
  • Chromatography, High Pressure Liquid
  • Dependovirus / genetics
  • Disease Models, Animal
  • Disease Progression
  • Dopamine / metabolism
  • Dopaminergic Neurons / metabolism*
  • Dopaminergic Neurons / pathology
  • ELAV Proteins / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Gene Expression Regulation / genetics
  • Genetic Vectors / physiology*
  • Green Fluorescent Proteins / genetics
  • Humans
  • Levodopa / pharmacology
  • Levodopa / therapeutic use
  • Mesencephalon / pathology*
  • Nerve Tissue Proteins / metabolism
  • Neurodegenerative Diseases / etiology
  • Neurodegenerative Diseases / genetics*
  • Parkinson Disease / complications
  • Parkinson Disease / drug therapy
  • Parkinson Disease / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Regulatory Elements, Transcriptional / genetics
  • Stereotyped Behavior / drug effects
  • Stereotyped Behavior / physiology
  • Time Factors
  • Tyrosine 3-Monooxygenase / metabolism
  • Vesicular Monoamine Transport Proteins / metabolism
  • alpha-Synuclein / genetics*
  • alpha-Synuclein / metabolism


  • Antiparkinson Agents
  • ELAV Proteins
  • Nerve Tissue Proteins
  • Vesicular Monoamine Transport Proteins
  • alpha-Synuclein
  • Green Fluorescent Proteins
  • Levodopa
  • Amphetamine
  • Tyrosine 3-Monooxygenase
  • Dopamine