Preclinical Models of Parkinson’s Disease

AAV α-synuclein overexpressing non-human primate

α-Synuclein is the major constituent protein of aggregates in Lewy bodies, the pathological hallmark of Parkinson’s disease. Viral delivery of α-synuclein to the substantia nigra of non-human primates (Macaca fascicularis) produces a slowly developing degeneration of dopaminergic neurons in the substantia nigra with pathology similar to that observed in people with Parkinson’s disease.

Model Overview

AAV1/2-A53T-α-synuclein vectors are injected bilaterally into the substantia nigra of macaques using MRI-based stereotactic techniques. Four injection sites per hemisphere are used to ensure complete viral coverage of the substantia nigra. Degeneration of dopaminergic neurons occurs over several weeks allowing test compounds to be evaluated for disease modifying potential. Some implementations of the model provide behavioural and imaging deficits, in addition to pathology readouts.

Robust loss on dopaminergic endpoints

Dopaminergic cell loss develops over time so that at 17 weeks postsurgery, there is a 4050% loss of striatal dopamine and tyrosine hydroxylase positive cells in the substantia nigra.

Test compounds can reverse AAV αSyn induced loss of dopamine

The loss of striatal dopamine that occurs over 17 weeks post-surgery can be significantly attenuated by daily administration of a known autophagy enhancer (trehalose) demonstrating that compounds that slow disease progression can be evaluated in this model.

PET imaging allows in-life assessment of dopaminergic cell loss

Striatal levels of markers of the dopaminergic system (DAT and VMAT) can be imaged throughout longitudinal studies – allows the effect of compounds to be followed over time.

MRI registered to CT
11C-CFT PET scan 
(DAT) 

Experimental readouts

  • Behavioural – Behavioural assessments include the monkey parkinsonian disability rating scale, the monkey equivalent of the clinical rating scales used to assess in people with Parkinson’s disease. Additional behavioural endpoints include home-cage activity, observation-cage activity and fine motor control.
  • Post mortem Routine post mortem analyses include striatal dopamine and dopamine transporter (DAT) and the number of number of TH+ve cells in the substantia nigra. Additional post-mortem measures can be incorporated at the request of the client.
  • Imaging – We offer both MRI and PET imaging that allows longitudinal measurement of markers of dopaminergic function and metabolism. 
  • Pharmacokinetics, safety and blood chemistry – Can be incorporated into all studies. Blood and CSF can be sampled throughout the study and terminal samples of brain and other tissues can be collected. Functional observational battery and blood chemistry can be used to assess off target effects and adverse effects.

Our sites and facilities

World class facilities, global connections

Atuka’s partners benefit from experienced scientists using advanced technologies at leading-edge research facilities in Canada and China.

Suzhou, China

  • Macaque in vivo facility
  • In vivo imaging
  • Surgical studies
  • Bioanalytical services
  • Behavioural studies

Toronto, Canada

  • Rodent in vivo laboratory 
  • In vitro laboratory 
  • Administrative office 

Get the latest science from Atuka

Sign up to receive our quarterly newsletter featuring the latest developments in Parkinson’s disease research.

List Signup