|Loss of α-Synuclein Does Not Affect Mitochondrial Bioenergetics in Rodent Neurons.
|Year of Publication
|Pathak D, Berthet A, Bendor JT, Yu K, Sellnow RC, Orr AL, Nguyen MK, Edwards RH, Manfredsson FP, Nakamura K
|alpha-Synuclein, Animals, Dopamine, Hippocampus, Mice, Knockout, Mitochondria, Neurons, Parkinson Disease, Synapses
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 . 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.
|PubMed Central ID
|R01 NS091902 / NS / NINDS NIH HHS / United States
R01 NS062715 / NS / NINDS NIH HHS / United States
C06 RR018928 / RR / NCRR NIH HHS / United States