Increased α-synuclein (αsyn) and mitochondrial dysfunction play central roles in the pathogenesis of Parkinson’s disease (PD), and lowering αsyn is under intensive investigation as a therapeutic strategy for PD. Increased αsyn levels disrupt mitochondria and impair respiration, while reduced αsyn protects against mitochondrial toxins, suggesting that interactions between αsyn and mitochondria influences the pathologic and physiologic functions of αsyn. However, we do not know if αsyn affects normal mitochondrial function or if lowering αsyn levels impacts bioenergetic function, especially at the nerve terminal where αsyn is enriched. To determine if αsyn is required for normal mitochondrial function in neurons, we comprehensively evaluated how lowering αsyn affects mitochondrial function. We found that αsyn knockout (KO) does not affect the respiration of cultured hippocampal neurons or cortical and dopaminergic synaptosomes, and that neither loss of αsyn nor all three (α, β and γ) syn isoforms decreased mitochondria-derived ATP levels at the synapse. Similarly, neither αsyn KO nor knockdown altered the capacity of synaptic mitochondria to meet the energy requirements of synaptic vesicle cycling or influenced the localization of mitochondria to dopamine (DA) synapses in vivo. Finally, αsyn KO did not affect overall energy metabolism in mice assessed with a Comprehensive Lab Animal Monitoring System. These studies suggest either that αsyn has little or no significant physiological effect on mitochondrial bioenergetic function, or that any such functions are fully compensated for when lost. These results implicate that αsyn levels can be reduced in neurons without impairing (or improving) mitochondrial bioenergetics or distribution.
Significance Statement Parkinson’s disease (PD) is characterized by mitochondrial dysfunction and the accumulation of α-synuclein (αsyn), and lowering αsyn levels is a leading therapeutic strategy for PD that is already under clinical investigation. However, because αsyn and mitochondria have intersecting functions, we must understand the impact of lowering αsyn on mitochondrial function. We analyzed the effects of lowering αsyn on mitochondrial bioenergetics, particularly at the nerve terminal where αsyn concentrates. We found that loss of αsyn does not impact the intrinsic bioenergetic function of mitochondria, suggesting that αsyn does not normally influence respiration, and that αsyn levels can likely be lowered without affecting mitochondrial function in PD.
Authors report no conflict of interest.
This work was supported by the Joan and David Traitel Family Trust, the Michael J. Fox Foundation for Parkinson’s Research, a Burroughs Wellcome Fund Medical Scientist Career Award and NIH RO1NS091902 to KN, a Cahill Family endowment and NIH R01NS062715 to RHE, and NIH RR18928 to the Gladstone Institutes.