In vivo models of Parkinson’s disease – Mammalian models
Evidence indicates an important role of mitochondrial dysfunction in sporadic Parkinson’s disease (PD) and familial forms of PD are often linked to genes involved in the mitochondrial function. In addition, a large number of neurotoxins that affect the mitochondrial respiration chain induce the death of dopaminergic cells.
It has also been shown that dopaminergic neurons of PD patients contain an elevated number of somatic mutations in mitochondrial DNA (mtDNA), which affect the mitochondrial respiration chain.
To investigate whether mitochondrial dysfunction plays a role in the etiology of PD causing neuronal cell death (primary role) or if it is a consequence of degenerating neurons (secondary role), a conditional knock-out mouse with a disruption in a gene fundamental for mtDNA maintenance, the mitochondrial transcription factor A (Tfam), specifically in midbrain dopaminergic neurons, has been developed: the MitoPark mouse.
Tfam is involved in mitochondrial biogenesis and mtDNA maintenance; it stabilizes mtDNA and regulates copy number. In the absence of Tfam a progressive deficiency in mitochondrial respiratory chain is observed followed by cell death.
To generate the MitoPark mouse model, knock-in mice expressing Cre recombinase under the control of the dopaminergic transporter (DAT) were crossed with mice bearing loxP recombination sites flanking the Tfam gene (TfamloxP). In this way Tfam deletion is directed only in cells expressing DAT.
|Species||Gene Knock out||Mouse genotype||Neurodegeneration (Y/N)||Link|