Dopaminergic but not cholinergic neurodegeneration is correlated with gait disturbances in PINK1 knockout rats

Behav Brain Res. 2022 Jan 24:417:113575. doi: 10.1016/j.bbr.2021.113575. Epub 2021 Sep 14.

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by gait dysfunction in later stages of the disease. PD hallmarks include a decrease in stride length, run speed, and swing time; an increase in stride time, stance time, and base of support; dopaminergic degeneration in the basal ganglia; and cholinergic degeneration in the pedunculopontine nucleus (PPN). A progressive animal model of PD is needed to identify treatments for gait dysfunction. The goal of this study was to quantify progressive gait degeneration in PTEN-induced putative kinase 1 knockout (P1KO) rats and investigate neurodegeneration as potential underlying mechanisms. Gait analysis was performed in male P1KO and wild-type rats at 5 and 8 months of age and immunohistochemical analysis at 8 months. Multiple parameters of volitional gait were measured using a runway system. P1KO rats exhibited significant gait deficits at 5 months, but not 8 months. Gait abnormalities improved over time suggesting compensation during behavioral testing. At 8 months a 15% loss of tyrosine hydroxylase (TH) in the striatum, a 27% loss of TH-positive cells in the substantia nigra pars compacta, and no significant loss of choline acetyltransferase-positive cells in the PPN was found. Dopaminergic cell loss may contribute to gait deficits in the P1KO model, but not cholinergic cell loss. The P1KO rat with the greatest dopamine loss exhibited the most pronounced PD-like gait deficits, highlighting variability within the model. Further analysis is required to determine the suitability of the P1KO rat as a progressive model of gait abnormalities in PD.

Keywords: Dopamine; Gait disturbances; PTEN-induced putative kinase 1 knockout; Parkinson’s disease; Pedunculopontine nucleus; Phosphate buffered saline; Substantia nigra pars compacta; Ventral tegmental area.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corpus Striatum / metabolism
  • Disease Models, Animal
  • Dopaminergic Neurons* / metabolism
  • Dopaminergic Neurons* / pathology
  • Gait Disorders, Neurologic
  • Male
  • Parkinson Disease / physiopathology
  • Pars Compacta / metabolism
  • Protein Kinases
  • Rats
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • Tyrosine 3-Monooxygenase
  • Protein Kinases
  • PTEN-induced putative kinase