Progressive parkinsonism due to mitochondrial impairment: Lessons from the MitoPark mouse model

Abstract

The cardinal pathophysiological finding of Parkinson's disease (PD) is a chronic, progressive degeneration of dopamine (DA) neurons in the substantia nigra, which is responsible for the motor and some of the non-motor symptomatology. While the primary causes of nigrostriatal degeneration are hotly debated, considerable evidence supports a central role for impaired mitochondrial function. Postmortem analysis of PD patients reveals impaired respiratory chains and increased mutations of mitochondrial DNA (mtDNA), in addition to increased markers of oxidative stress indicative of mitochondrial impairment. Most animal models of PD, both genetic and toxin-based, target some component of mitochondrial function to reproduce aspects of the human disease. One model that continues to gain attention is the MitoPark mouse, created through a cell type-specific knockout of mitochondrial transcription factor A specifically in midbrain DA neurons. This model effectively recapitulates the slowly developing, adult onset motor decline seen in PD due to mass loss of DA neurons. MitoPark mice therefore represent an effective tool for studying the sequence of events that occurs in the early stages of DA neuron degeneration following mitochondrial impairment, as well as for testing the efficacy of potential disease-modifying therapies in a progressive model of neurodegeneration. A targeted review of key findings from MitoPark mice has not been published since the early years following the initial report of the model in 2007. The current review synthesizes findings from several groups that are exploring MitoPark mice and discusses implications for the future identification of disease-modifying treatments for PD.