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Property "Has-20abstract" (as page type) with input value "Mitochondrial-20dysfunction-20and-20oxidative-20stress-20are-20among-20the-20earliest-20and-20most-20frequently-20reported-20pathogenic-20changes-20in-20late-2Donset-20neurodegenerative-20diseases,-20most-20notably-20Parkinson’s-20disease-20(PD).-20However,-20the-20etiological-20significance-20of-20aberrant-20mitochondrial-20signaling-20has-20remained-20a-20mystery,-20due,-20in-20part,-20to-20our-20limited-20understanding-20of-20mitochondrial-20genetics,-20the-20difficulty-20of-20manipulating-20it-20in-20mammalian-20models,-20and-20the-20lack-20of-20biomarkers-20to-20track-20mitochondrial-20dysfunction-20in-20the-20brain-20-27-27in-20vivo-27-27.-20The-20recent-20advances-20described-20herein-20finally-20address-20these-20problems,-20and-20provide-20new-20promise-20for-20early-20detection-20and-20treatment-20of-20late-2Donset-20neurodegenerative-20diseases.-0A-20-20-0AThe-20mitochondrial-20DNA-20(mtDNA)-20gene-20most-20consistently-20implicated-20in-20PD-20encodes-20the-20ND6-20subunit-20of-20complex-20I.-20ND6-20mutations-20have-20been-20found-20in-20basal-20ganglia-20degeneration-20leading-20to-20dystonia-20and-20Leigh-20syndrome,-20and-20ND6-20transcripts-20are-20decreased-20in-20PD-20mouse-20models-20and-20patients.-20Furthermore,-20mitochondrial-20complex-20I-20is-20the-20molecular-20target-20of-20endogenous-20(alpha-2Dsynuclein)-20and-20environmental-20PD-20risk-20factors-20(MPTP,-20rotenone,-20paraquat),-20which-20may-20explain-20decreased-20complex-20I-20activity-20in-20the-20blood,-20muscle,-20and-20autopsied-20brains-20of-20PD-20patients.-20In-20light-20of-20these-20findings,-20we-20introduced-20a-20homoplasmic,-20missense-20mutation-20in-20the-20ND6-20subunit-20of-20complex-20I,-20creating-20the-20first-20transgenic-20mouse-20with-20a-20specific,-20pathogenic-20mtDNA-20variant,-20ND6-3Csup-3EP25L-3C-2Fsup-3E.-20Mitochondrial-20bioenergetics-20is-20shifted-20by-20the-20ND6-3Csup-3EP25L-3C-2Fsup-3E-20mutation,-20which-20impairs-20complex-20I-20activity,-20increased-20mitochondrial-20reactive-20oxygen-20species-20(mtROS)-20production-20in-20the-20“forward”-20direction,-20but-20negates-20ROS-20via-20“reverse-20electron-20transfer”,-20and-20has-20no-20effect-20on-20ATP.-20These-20bioenergetic-20changes-20led-20to-20an-20accumulation-20of-20defective-20synaptic-20mitochondria,-20increased-20alpha-2Dsynuclein-20and-20neuroinflammation,-20killed-20dopaminergic-20neurons,-20and-20recapitulated-20the-20full-20spectrum-20clinical-20PD-20symptoms,-20from-20REM-20defects-20to-20depression,-20motor-20impairments,-20and-20finally-20cognitive-20decline.-20The-20ND6-3Csup-3EP25L-3C-2Fsup-3E-20mouse-20provides-20the-20first-20direct-20demonstration-20that-20mtDNA-20variation-20alone-20is-20sufficient-20to-20induce-20Parkinsonian-20pathology-20in-20an-20otherwise-20unaffected-20host.-20We-20are-20now-20using-20this-20model-20system-20to-20establish-20mitochondrial-20biomarkers-20for-20the-20preclinical-20and-20prodromal-20phases-20of-20late-2Donset-20PD.-20-20We-20have-20validated-20the-20first-20superoxide-2Dsensitive-20radiotracer-20for-20detection-20of-20oxidative-20stress-20-27-27in-20vivo-27-27.-20The-20results-20prove-20that-20this-20novel-20probe-20crosses-20the-20blood-2Dbrain-20barrier-20and-20detects-20a-2033-25-20ROS-20increase-20in-20the-20ND6-3Csup-3EP25L-3C-2Fsup-3E-20brain,-20which-20mirrors-20the-20increase-20seen-20in-20isolated-20brain-20mitochondria.-20These-20results-20establish-20the-20first-20method-20for-20analysis-20of-20oxidative-20stress-20in-20the-20living-20brain,-20which-20will-20serve-20as-20a-20powerful-20tool-20to-20determine-20the-20role-20of-20mitochondrial-20dysfunction-20in-20etiology-20of-20neurodegenerative-20disease.-20Using-20a-20multi-2Dtiered-20approach,-20-20we-20are-20moving-20beyond-20decades-20of-20correlative-20data-20to-20establish-20conclusive-20proof-20of-20causation-20for-20mitochondrial-20genetics,-20bioenergetic-20dysfunction,-20and-20oxidative-20stress-20in-20the-20pathogenesis-20of-20age-2Drelated-20disease." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.

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