Preclinical Models of Parkinson’s Disease

PFF α-synuclein over-expressing rodent

α-Synuclein (aSyn) is the major constituent protein of aggregates in Lewy bodies, the pathological hallmark of Parkinson’s disease. Intra-striatal administration of α-synuclein preformed fibrils (PFFs) to rats or mice produces a propagating pathology that generates pSer129-aSyn deposits throughout interconnected parts of the brain. The pathology produced is analogous to that observed in people with Parkinson’s disease.

Model Overview

Mouse aSyn PFFs are injected bilaterally into the striatum of rats or mice using stereotaxic techniques.Accumulations of pSer129-aSyn can be seen over the course of 30-, 60-, and 120-days allowing test compounds to be evaluated for their ability to prevent uptake of PFFs and the formation of pathologic forms of aSyn. 

pSer129-aSyn-ir
Substantia nigra
Hippocampus
Prefrontal Cortex
Parietal cortex

Deposits of aSyn are resistant to PK-digestion and are Thio-S positive

PFF-aSyn results in reductions of striatal dopamine

At day 30 and persistent out to day 120, striatal dopamine levels are significantly reduced in PFF-aSyn inoculated mice compared to monomer-aSyn.

BilatePFF-aSyn results in reductions of SN dopamine neurons

At day 120, SN dopamine neurons are significantly reduced in PFF-aSyn inoculated rats compared to monomer-aSyn.

Experimental readouts

  • Post-mortem – Routine post-mortem analyses include striatal dopamine, TH and dopamine transporter (DAT) levels and assessments of pSer129-aSyn density in various midbrain and forebrain ROIs. The number of pSer129-aSyn positive cells in the substantia nigra can be quantified by stereological cell counting to assess pathological aSyn clearing strategies. Additional post-mortem measures can be incorporated at the request of the client.
  • Target engagement Demonstration of target engagement can often be incorporated into the study design aiding translation from rodent studies to non-human primate studies and ultimately to clinical studies.
  • Pharmacokinetics – Can be incorporated into all studies. Blood can be sampled throughout the study and terminal samples of CSF and brain and other tissues can be collected.

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