Disorders of the Nervous System Loss of -Synuclein Does Not Affect Mitochondrial Bioenergetics in Rodent Neurons

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