General Information

Rat: Long Evans

Microinjection of engineered zinc finger nucleases (ZFNs) in embryos was used to generate PINK1 gene knockout rats. The ZFN causes a 26bp deletion in exon 4 resulting in loss of PINK1 protein expression in homozygous Pink1-/- rats.

Corresponding human genotype: Autosomal recessive mutation in the PINK1 gene causing a loss-of-function of the protein and leading to early-onset Parkinson’s disease (PARK6).

Mutated gene: PINK1

References: PMID 24969022, PMID 26234713, PMID 26577653, PMID 25421206

Loss of dopaminergic neurons

A progressive, age-dependent loss of TH-positive neurons is observed in the SN

  • 4 months: No significant loss of TH-positive neurons is observed compared to wild type rats
  • 6 months: 25% reduction in the number of TH-positive neurons
  • 8 months: 50% reduction in the number of TH-positive neurons. Studies involving daily handling of animals for behavioural studies show no evidence of dopaminergic cell loss in the SN.

No changes in the density of TH-positive terminals is observed in the striatum at any time point (4, 6 and 8 months).

Dopamine Homeostasis

  • 8 months: 2-3-fold increase in the levels of dopamine and dopamine metabolites, as well as of serotonin (5-HT) are observed. Neurotransmitters turnovers are not altered.

Inclusions

  • 4, 6 and 8 months: no changes in alpha-synuclein expression. Some aggregate formation is observed at 8 months but is not consistent across studies.

Motor Behaviours

  • 4 months: no motor deficits or alterations are observed.
  • 6 and 8 months: no changes in accelerating rotarod performances are detected.
    Significant reduction of rearing frequency and total distance travelled in the open field test are detected.
    Reduction of hindlimb (not forelimb) grip strength.
  • 8 months: aged-dependent impairment in gait movements and air-righting reflex (not detected at 4 and 6 months). Dysfunctions in motor coordination in the tapered balance beam test are observed.

Response to dopaminergic treatment

  • Not reported

Non motor Behaviours

  • 2-8 months: progressive vocalization (reduced loudness, peak frequency, band width) and oromotor (tongue function) alterations  are observed;  these alterations are present prior to the onset of limb deficits and dopaminergic cell loss in the SN. Inconsistent biting abilities are also observed. Intensive vocal exercise therapy can improve the deficits at early stages (2 months) but not at later time points (4, 6 and 8 months).

Electrophysiology

  • Not reported

Neuroinflammation

  • Not reported

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