Aging is considered as a major risk factor for Parkinson’s disease (PD) and can be defined as a gradual decline in the ability of biological systems to efficiently renew structural and functional components, which may lead to perturbations in energetic homeostasis. AMPK is a heterotrimeric enzyme that is both a critical sensor and regulator of the energetic status of the cell. The activity of AMPK may progressively decline with age, therefore contributing to the metabolic perturbations that underlie neurodegenerative diseases. Here, we explore the mutual interplay between α-synuclein (α-syn), a key factor in PD patholo-gy, and AMPK, using a genetic rat model based on overexpression of human α-syn. More specifi-cally, we explore how the expression of various genetic variants of the catalytic AMPK α subunit determines the effects of α-syn overexpression, both in vitro and in vivo. We show that overex-pression of either AMPK α1 and α2 to increase AMPK activity, have partial neuroprotective effects against human α-syn toxicity in the nigrostriatal system. Remarkably, chronic, low level of AMPK activity, induced via overexpression of a mutated form of AMPKα (T172D AMPKα1), most effec-tively prevents the loss of dopamine neurons as well as the motor impairments caused by α-syn accumulation. Furthermore, only T172D AMPKα1 leads to the significant clearance of aggregated α-syn in the dopamine axonal fibers. In vitro results indicate that α-syn accumulation in primary cortical neurons leads to increased autophagic activity and a decline in the number of mitochondrial DNA copies. When AMPKα subu-nits are overexpressed simultaneously with α-syn, an increased in the mitochondrial mass is ob-served, together with a rescue of the autophagic response caused by α-syn overexpression. Re-markably, neurons overexpressing the T172D AMPKα1 variant show an intermediate phenotype, where α-syn-induced autophagy is still observed, although there is no more changes in mitochondrial parameters caused by α-syn overexpression. Finally, using the same human α-syn genetic model of PD, we show neuroprotective effects us-ing a diet supplemented with urolithin, a polyphenolic compound known to activate AMPK. Nigro-striatal dopaminergic neurons are significantly rescue from α-syn toxicity in rats fed with urolithin, underlining the importance of AMPK signaling in prospective PD therapy.