Treadmill exercise intervention improves gait and postural control in alpha-synuclein mouse models without inducing cerebral autophagy

Georgia Minakaki, Fabio Canneva, Frédéric Chevessier, Frederik Bode, Stefanie Menges, Ivanna K. Timotius, Liubov S. Kalinichenko, Holger Meixner, Christian P. Müller, Bjoern M. Eskofier, Nicolas Casadei, Olaf Riess, Rolf Schröder, Jürgen Winkler, Wei Xiang, Stephan von Hörsten, Jochen Klucken*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

23 Citations (Scopus)

Abstract

Gait and postural control dysfunction are prototypical symptoms compromising quality of life for patients with Parkinson's disease (PD). Hallmarks of cellular pathology are dopaminergic degeneration and accumulation of the cytosolic protein alpha-synuclein, linked to impaired autophagy-lysosome pathway (ALP) clearance. Physical exercise improves gait in PD patients and motor function in rodent lesion models. Moreover, exercise is considered neuroprotective and ALP induction has been reported, e.g. in human skeletal muscle, rodent peripheral and cerebral tissues. A combined analysis of how distinct exercise paradigms affect motor and central biochemical aspects of PD could maximize benefits for patients. Here we examine the effect of 4 weeks treadmill exercise intervention in 7–8 month non-lesioned mice on a) distinct gait categories, b) ALP activity, c) dopaminergic and alpha-synuclein homeostasis. The study includes wild type, alpha-synuclein knockout, and mice exclusively expressing human alpha-synuclein. Parameters of gait regularity and stability, activity, and dynamic postural control during unforced walk, were assessed by an automated system (CatWalk XT). At baseline, alpha-synuclein mouse models exhibited irregular and less active gait, with impaired dynamic postural control, compared to wild type mice. Treadmill exercise particularly improved speed and stride length, while increasing dual diagonal versus three-paw body support in both the alpha-synuclein knockout and transgenic mice. Biochemical analyses showed higher striatal tyrosine hydroxylase immuno-reactivity and reduced higher-order alpha-synuclein species in the cerebral cortex. However, no significant cerebral ALP induction was measured. In summary, treadmill exercise improved gait activity and postural stability, and promoted dopaminergic and alpha-synuclein homeostasis, without robustly inducing cerebral ALP.

Original languageEnglish
Pages (from-to)199-215
Number of pages17
JournalBehavioural Brain Research
Volume363
DOIs
Publication statusPublished - 2 May 2019
Externally publishedYes

Keywords

  • Alpha-synuclein
  • Autophagy
  • Instrumented gait analysis
  • Mouse gait pattern
  • Parkinson's disease
  • Treadmill exercise

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