Role of mitochondria in neurodegenerative diseases

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

We have explored the role of mitochondria in Parkinson's disease (PD). At least two gene products mutated in familial PD, PINK1 and Parkin, are now known to mediate autophagic removal of defective mitochondria suggesting that one cause of PD is an impairment of mitochondrial quality control. PINK1 is a kinase located on mitochondria whereas Parkin is an E3 ubiquitin ligase normally located in the cytosol. Upon mitochondrial damage Pink1 recruits cytosolic Parkin to mitochondria to mediate mitophagy revealing a cell biology pathway in mammalian cells where Pink1 works upstream of Parkin. PINK1 acts as a sensor of mitochondria function and Parkin induced the elimination of those damaged mitochondria. An animal model that accumulates mitochondrial DNA mutations corroborates the model that Parkin mediates quality control and rescues neurons from damaged mitochondria. We preformed full genome RNAi screens to identify gene products participating in PINK1 recruitment of Parkin to mitochondria and Parkin stimulation of autophagosome engulfment of mitochondria. 1) The genetic screens led us to identify a strong inflammatory phenotype in both Parkin-/- and PINK1-/- mice when crossed with Mutator mice, which accumulate mitochondrial DNA mutations with age. In collaboration with a leading German group with large cohorts of PINK1 and Parkin mutant PD patients we discovered that people with biallelic Parkin mutations display elevated circulating cytokines at levels higher than either healthy controls or those with idiopathic PD. Furthermore, these biallelic Parkin and PINK1 patients had higher circulating levels of mitochondrial DNA than either healthy controls or idiopathic PD patients. These results support the model that PINK1- and Parkin-mediated mitophagy restrains innate immunity as a way to prevent PD. 2) In contrast to mice and man, recessive mutations in Parkin in Drosophila melanogaster display severe physical and locomotion defects caused by excess mitochondria damage, leading to muscle defects and progressive degeneration of dopaminergic neurons. Innate immunity pathways including STING and NF-kB pathways are conserved in flies, however, the role of innate immune signaling in Pink1/Parkin mutant fly pathology has not been established. We found the conserved immunity regulator STING mediates the Parkin loss of function phenotypes. Two genetically independent STING and Parkin double knockout strains were generated. Deletion of STING with significantly reduces the penetrance of the major Parkin null fly phenotypes including flight muscle defects, wing posture, and climbing ability. Surprisingly, the underlying mitochondria morphology defects in Parkin mutant flies were also suppressed in these double mutant lines. 3) We explored how STING, functioning downstream of mitochondrial damage and mtDNA release into the cytosol, activates innate immunity. We discovered a new and unanticipated function of STING in activating the lipidation of LC3, which is classically thought to be linked to double membrane autophagosomes. Instead of inducing autophagy as had been the dominant model, we found STING lipidates LC3 onto single membrane Golgi associated membranes. The innate immune function of this novel step in STING activity is being explored by us and others.