Mitochondrial quality control is essential for the long-term survival of postmitotic neurons. The E3 ubiquitin ligase Parkin promotes the degradation of damaged mitochondria via mitophagy and mutations in Parkin are a major cause of early-onset Parkinson’s disease (PD). Surprisingly however, mice deleted for Parkin alone are rather asymptomatic for PD-related pathology, suggesting that other complementary or redundant mitochondrial quality control pathways may exist in neurons. Mitochondrial damage is often accompanied by the release of toxic proteins such as cytochrome c. We have reported that once in the cytosol, cytochrome c is targeted for degradation by the E3 ligase CUL9 in neurons. Here we examined whether CUL9 and Parkin cooperate to promote optimal neuronal survival in vivo. We generated mice deficient for both Cul9 and Parkin and examined them for PD-related phenotypes. Specifically, we conducted assays to examine behavioural deficits (locomotor, sensory, memory and learning) and loss of dopaminergic neurons in both males and females. Our results show that the loss of Cul9 and Parkin together did not enhance the effect of Parkin deficiency alone. These results indicate that while both Parkin and CUL9 participate in mitochondrial quality control, neurons likely have multiple redundant mechanisms to ensure their long-term survival.
We thank Viktoriya Nikolova at the UNC Mouse Behavioural Phenotyping Laboratory for her technical assistance. This work was supported by a Rapid Response Innovation Award (ID 9056) from the Michael J Fox Foundation for Parkinson’s Research and by the NIH Grant GM118331 to M.D. V.J. was supported by Training in translational Research in Neurology NIH Fellowship 2T32NS007480. The Tansey laboratory is supported by NIH/NIA 1R01 AG057247, NIH/NINDS 5R01 NS092122, NIH/NIA 3RF1 AG051514-01, and the Norman Fixel Institute for Neurological Diseases to M.G.T. The UNC Mouse Behavioural Phenotyping Laboratory is supported by a grant from the National Institute of Child Health and Human Development (NICHD), U54-HD079124. The Neuroscience Microscopy Core Facility is supported, in part, by funding from the NIH-NINDS Neuroscience Center Support Grant P30 NS045892 and the NIH-NICHD Intellectual and Developmental Disabilities Research Center Support Grant U54 HD079124.
E.H. conducted the in vitro experiments and prepared the mice cohorts. V.S. and A.N. helped with generating the Cul9, Parkin double KO mice. V.J and M.J.T. performed the stereological analysis and quantification of dopaminergic neurons. S.M. conducted and analysed the neurobehavioral assessments. M.D. outlined and supervised the project. E.H. and M.D. produced the final version of the manuscript.
- Diseases of the nervous system
- Parkinson's disease