Loss of α-Synuclein Does Not Affect Mitochondrial Bioenergetics in Rodent Neurons.

Increased alpha-synuclein (alpha syn) and mitochondrial dysfunction play central roles in the pathogenesis of Parkinson's disease (PD), and lowering alpha syn is under intensive investigation as a therapeutic strategy for PD. Increased alpha syn levels disrupt mitochondria and impair respiration, while reduced alpha syn protects against mitochondrial toxins, suggesting that interactions between alpha syn and mitochondria influences the pathologic and physiologic functions of alpha syn. However, we do not know if alpha syn affects normal mitochondrial function or if lowering alpha syn levels impacts bioenergetic function, especially at the nerve terminal where alpha syn is enriched. To determine if alpha syn is required for normal mitochondrial function in neurons, we comprehensively evaluated how lowering alpha syn affects mitochondrial function. We found that alpha syn knockout (KO) does not affect the respiration of cultured hippocampal neurons or cortical and dopaminergic synaptosomes, and that neither loss of alpha syn nor all three (alpha, beta and gamma) syn isoforms decreased mitochondria-derived ATP levels at the synapse. Similarly, neither alpha syn 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, alpha syn KO did not affect overall energy metabolism in mice assessed with a Comprehensive Lab Animal Monitoring System. These studies suggest either that alpha syn 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 alpha syn levels can be reduced in neurons without impairing (or improving) mitochondrial bioenergetics or distribution.