The cybrid model of sporadic Parkinson's disease

Patricia A. Trimmer, James P. Bennett
2009 Experimental Neurology  
Parkinson's disease (PD) is the eponym attached to the most prevalent neurodegenerative movement disorder of adults, derived from observations of an early nineteenth century physician and paleontologist, James Parkinson, and is now recognized to encompass much more than a movement disorder clinically or dopamine neuron death pathologically. Most PD (~90%) is sporadic (sPD), is associated with mitochondrial deficiencies and has been studied in cell and animal models arising from use of
more » ... ial toxins that unfortunately have not predicted clinical efficacy to slow disease progression in humans. We have extensively studied the cytoplasmic hybrid ("cybrid") model of sPD in which donor mtDNA's are introduced into and expressed in neural tumor cells with identical nuclear genetic and environmental backgrounds. sPD cybrids demonstrate many abnormalities in which increased oxidative stress drives downstream antioxidant response and cell death activating signaling pathways. sPD cybrids regulate mitochondrial ETC genes and gene ontology families like sPD brain. sPD cybrids spontaneously form Lewy bodies and Lewy neurites, linking mtDNA expression to neuropathology, and demonstrate impaired organelle transport in processes and reduced mitochondrial respiration. Our recent studies show that near-infrered laser light therapy normalizes mitochondrial movement and can stimulate respiration in sPD cybrid neurons, and mitochondrial gene therapy can restore respiration and stimulate mitochondrial ETC gene and protein expression. sPD cybrids have provided multiple lines of circumstantial evidence linking mtDNA to sPD pathogenesis and can serve as platforms for therapy development. sPD cybrid models can be improved by use of non-tumor human stem cell-derived neural precursor cells and by introduction of postmortem brain mtDNA to test its causality directly.
doi:10.1016/j.expneurol.2009.03.016 pmid:19328199 pmcid:PMC2735256 fatcat:jqe6hdop55f67cj67cpolvleqy