Modulating the catalytic activity of AMPK has neuroprotective effects against α-synuclein toxicity

Background: Metabolic perturbations and slower renewal of cellular components associated with aging increase the risk of Parkinson's disease (PD). Declining activity of AMPK, a critical cellular energy sensor, may therefore contribute to neurodegeneration. Methods: Here, we overexpress various genetic variants of the catalytic AMPK alpha subunit to determine how AMPK activity affects the survival and function of neurons overexpressing human alpha-synuclein in vivo. Results: Both AMPK alpha 1 and alpha 2 subunits have neuroprotective effects against human alpha-synuclein toxicity in nigral dopaminergic neurons. Remarkably, a modified variant of AMPK alpha 1 (T172D alpha 1) with constitutive low activity most effectively prevents the loss of dopamine neurons, as well as the motor impairments caused by alpha-synuclein accumulation. In the striatum, T172D alpha 1 decreases the formation of dystrophic axons, which contain aggregated alpha-synuclein. In primary cortical neurons, overexpression of human a-synuclein perturbs mitochondrial and lysosomal activities. Co-expressing AMPK alpha with alpha-synuclein induces compensatory changes, which limit the accumulation of lysosomal material and increase the mitochondrial mass. Conclusions: Together, these results indicate that modulating AMPK activity can mitigate alpha-synuclein toxicity in nigral dopamine neurons, which may have implications for the development of neuroprotective treatments against PD.