McManus 2016 Abstract MitoFit Science Camp 2016
|A multi-tiered mitochondrial approach to predictive biomarkers of neurodegenerative disease.|
McManus MJ (2016)
Mitochondrial dysfunction and oxidative stress are among the earliest and most frequently reported pathogenic changes in late-onset neurodegenerative diseases, most notably Parkinson’s disease (PD). However, the etiological significance of aberrant mitochondrial signaling has remained a mystery, due, in part, to our limited understanding of mitochondrial genetics, the difficulty of manipulating it in mammalian models, and the lack of biomarkers to track mitochondrial dysfunction in the brain in vivo. The recent advances described herein finally address these problems, and provide new promise for early detection and treatment of late-onset neurodegenerative diseases.
The mitochondrial DNA (mtDNA) gene most consistently implicated in PD encodes the ND6 subunit of complex I. ND6 mutations have been found in basal ganglia degeneration leading to dystonia and Leigh syndrome, and ND6 transcripts are decreased in PD mouse models and patients. Furthermore, mitochondrial complex I is the molecular target of endogenous (alpha-synuclein) and environmental PD risk factors (MPTP, rotenone, paraquat), which may explain decreased complex I activity in the blood, muscle, and autopsied brains of PD patients. In light of these findings, we introduced a homoplasmic, missense mutation in the ND6 subunit of complex I, creating the first transgenic mouse with a specific, pathogenic mtDNA variant, ND6P25L. Mitochondrial bioenergetics is shifted by the ND6P25L mutation, which impairs complex I activity, increased mitochondrial reactive oxygen species (mtROS) production in the “forward” direction, but negates ROS via “reverse electron transfer”, and has no effect on ATP. These bioenergetic changes led to an accumulation of defective synaptic mitochondria, increased alpha-synuclein and neuroinflammation, killed dopaminergic neurons, and recapitulated the full spectrum clinical PD symptoms, from REM defects to depression, motor impairments, and finally cognitive decline. The ND6P25L mouse provides the first direct demonstration that mtDNA variation alone is sufficient to induce Parkinsonian pathology in an otherwise unaffected host. We are now using this model system to establish mitochondrial biomarkers for the preclinical and prodromal phases of late-onset PD. We have validated the first superoxide-sensitive radiotracer for detection of oxidative stress in vivo. The results prove that this novel probe crosses the blood-brain barrier and detects a 33% ROS increase in the ND6P25L brain, which mirrors the increase seen in isolated brain mitochondria. These results establish the first method for analysis of oxidative stress in the living brain, which will serve as a powerful tool to determine the role of mitochondrial dysfunction in etiology of neurodegenerative disease. Using a multi-tiered approach, we are moving beyond decades of correlative data to establish conclusive proof of causation for mitochondrial genetics, bioenergetic dysfunction, and oxidative stress in the pathogenesis of age-related disease.
• O2k-Network Lab: US PA Philadelphia Wallace DC
Labels: MiParea: mt-Biogenesis;mt-density, mtDNA;mt-genetics Pathology: Parkinson's Stress:Oxidative stress;RONS
Enzyme: Complex I
Event: B3 MitoFit Science Camp 2016
Children's Hospital Philadelphia, PA, US. - [email protected]