AAV-Mediated Expression of Dominant-Negative ULK1 Increases Neuronal Survival and Enhances Motor Performance in the MPTP Mouse Model of Parkinson’s Disease

Dirk Balke, Lars Tatenhorst, Vivian Dambeck, Vinicius Toledo Ribas, Björn F. Vahsen, Uwe Michel, Mathias Bähr, Paul Lingor

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Loss of nigrostriatal projections by axonal degeneration is a key early event in Parkinson’s disease (PD) pathophysiology, being accountable for the lack of dopamine in the nigrostriatal system and resulting in motor symptoms such as bradykinesia, rigidity, and tremor. Since autophagy is an important mechanism contributing to axonal degeneration, we aimed to evaluate the effects of competitive autophagy inhibition in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD in vivo. Adeno-associated viral vector (AAV)–mediated overexpression of a dominant-negative form of the unc-51 like autophagy-initiating kinase (ULK1.DN) in the substantia nigra was induced 3 weeks before MPTP treatment. Analysis of motor behavior demonstrated a significant improvement of ULK1.DN expressing mice after MPTP treatment. Immunohistochemical analyses of dopaminergic nigral neurons and nigrostriatal projections revealed a significant protection from MPTP-induced neurotoxicity after ULK1.DN expression. Western blot analysis linked these findings to an activation of mTOR signaling. Taken together, our results indicate that expression of ULK1.DN can attenuate MPTP-induced axonal neurodegeneration, suggesting that ULK1 could be a promising novel target in the treatment of PD.

Original languageEnglish
Pages (from-to)685-697
Number of pages13
JournalMolecular Neurobiology
Volume57
Issue number2
DOIs
StatePublished - 1 Feb 2020
Externally publishedYes

Keywords

  • Autophagy
  • Axonal degeneration
  • MPTP mouse model
  • Parkinson’s disease
  • ULK1

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