title: Striatal dysfunctions associated with mitochondrial DNA damage in dopaminergic neurons in a mouse model of Parkinson's disease.
abstract: Parkinson's disease (PD) is one of the most common progressive neurodegenerative disorders, characterized by resting tremor, rigidity, bradykinesia, and postural instability. These symptoms are associated with massive loss of tyrosine hydroxylase-positive neurons in the substantia nigra (SN) causing an estimated 70-80% depletion of dopamine (DA) in the striatum, where their projections are located. Although the etiology of PD is unknown, mitochondrial dysfunctions have been associated with the disease pathophysiology. We used a mouse model expressing a mitochondria-targeted restriction enzyme, PstI or mito-PstI, to damage mitochondrial DNA (mtDNA) in dopaminergic neurons. The expression of mito-PstI induces double-strand breaks in the mtDNA, leading to an oxidative phosphorylation deficiency, mostly due to mtDNA depletion. Taking advantage of a dopamine transporter (DAT) promoter-driven tetracycline transactivator protein (tTA), we expressed mito-PstI exclusively in dopaminergic neurons, creating a novel PD transgenic mouse model (PD-mito-PstI mouse). These mice recapitulate most of the major features of PD: they have a motor phenotype that is reversible with l-DOPA treatment, a progressive neurodegeneration of the SN dopaminergic population, and striatal DA depletion. Our results also showed that behavioral phenotypes in PD-mito-PstI mice were associated with striatal dysfunctions preceding SN loss of tyrosine hydroxylase-positive neurons and that other neurotransmitter systems [noradrenaline (NE) and serotonin (5-HT)] were increased after the disruption of DA neurons, potentially as a compensatory mechanism. This transgenic mouse model provides a novel model to study the role of mitochondrial defects in the axonal projections of the striatum in the pathophysiology of PD.
authors: Neuroscience Graduate Program, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
authors: Alicia M
authors: AM
authors: Pickrell
authors: Milena
authors: M
authors: Pinto
authors: Aline
authors: A
authors: Hida
authors: Carlos T
authors: CT
authors: Moraes
mesh_terms: D000818:Animals; D002452:Cell Count; D003342:Corpus Striatum / Q000378:metabolism*; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D004298:Dopamine