Regulation of the autophagy protein ULK1 in the MPTP mouse model of Parkinson's disease

Parkinson’s disease (PD) is a widespread neurodegenerative condition. Owing to the absence of suitable biomarkers, a diagnosis can only be made upon onset of clinical symptoms like tremor, rigidity or bradykinesia. They occur mainly due to degeneration of the nigrostriatal system, but other brain areas and autonomic nerves are also affected by PD. The demise of dopaminergic neurons and the presence of Lewy bodies in affected neuronal somas and axons represent the most recognized histopathologic hallmark of PD. With exception of the monogenetic forms of PD, its etiology is multifactorial and based on gene-environment interaction. Autophagy, as a highly conserved homeostatic and vital process, is dysregulated in Parkinson diseased brains and contributes to axonal and neuronal death. Therefore, the present study aimed to assess neuroprotective and neurorestorative properties of competitive autophagy inhibition via Adeno-associated virus-mediated ULK1.DN gene expression in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. It could be demonstrated that ULK1.DN expression was able to rescue dopaminergic cell bodies from MPTP-induced neurotoxicity two weeks post MPTP treatment. Furthermore, also dopaminergic striatal fibers were significantly protected as compared to controls. Western blot analysis confirmed a downregulation of autophagy by ULK1.DN overexpression and showed a significant activation of Mammalian target of rapamycin (mTOR) signaling. While striatal dopamine levels could not be rescued by ULK1.DN gene expression, a beneficial effect in motor behavior in the cylinder rearing test was observed six weeks post MPTP treatment, pointing towards beneficial long-term effects of ULK1.DN expression. Part of a possible explanation for these findings may be the modulation of extrastriatal dopaminergic projections and an enhanced sprouting and synapse formation. Taking all these aspects into consideration, competitive autophagy inhibition via ULK1.DN expression shows promising neuroprotective properties as well as beneficial long-term effects on motor skills. Consequently, competitive autophagy inhibition may be considered a promising target in future therapeutic approaches of PD.2022-11-2