AAV-Mediated Expression of Dominant-Negative ULK1 Increases Neuronal Survival and Enhances Motor Performance in the MPTP Mouse Model of Parkinson’s Disease
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.
KeywordsULK1 Autophagy Axonal degeneration MPTP mouse model Parkinson’s disease
Acute axonal degeneration
AMP-activated protein kinase
FAK family interacting protein of 200 kDa
High-performance liquid chromatography
Microtubule-associated proteins 1A/1B light chain 3B
- MPP +
Mechanistic target of rapamycin kinase
Substantia nigra pars compacta
Unc-51 like autophagy activating kinase
The authors thank Elisabeth Barski, Sabine Ceramella, and Barbara Müller for excellent technical support. We thank Sharon A. Tooze (Francis Crick Institute, London, UK) for providing the ULK1.DN plasmid.
D.B. and B.F.V. were supported by a scholarship from the Department of Neurology, University Medical Center Göttingen. V.T.R. was a fellow of the National Council for Scientific and Technological Development (CNPq), Brazil. L.T., V.D., M.B. and P.L. received funding from the Cluster of Excellence and DFG Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen.
Compliance with Ethical Standards
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in this study involving animals were in accordance with the ethical standards and followed the regulations of the animal research council at the University Medical Center Göttingen and legislation of the State of Lower Saxony, Germany (33.9-42502-04-16/2239).
This article does not contain any studies with human participants performed by any of the authors.
Conflict of Interest
The authors declare that they have no conflict of interest.
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