The motor symptoms of Parkinson’s disease (PD) result from the degeneration of substantia nigra dopamine (SN DA) neurons and the basal ganglia pathophysiology triggered by this loss. However, the mechanisms that underlie the progressive degeneration of SN DA neurons, the regional network pathophysiology this causes and PD symptoms are uncertain. A major obstacle to answering these questions is the lack of a progressive animal model of PD amenable to the application of advanced tools for the interrogation of neurons and neural networks. Recently, our group has developed a new mouse model of PD that overcomes this obstacle, giving us an extraordinary opportunity. The model is predicated on the observation that loss of functional mitochondrial complex I (MCI) – a critical element in the electron transport chain – is a common feature of the SN in PD patients. We found that knocking out the catalytic subunit of MCI (Ndufs2) in SN DA neurons leads to progressive, levodopa-responsive parkinsonism in mice. Importantly, in this so-called MCI-Park mouse, DA neuron pathology begins in nigrostriatal axons and then proceeds to the somatodendritic region - reproducing a key feature of human PD pathology. This human-like staging of pathology should provide clues not only to PD pathogenesis, but also to the roles played by regional network pathophysiology in the emergence of motor symptoms. By combining the expertise of the Surmeier and Bevan labs, we can rigorously characterize the mechanisms underlying the emergence of motor deficits in the MCI-Park model through a battery of complementary cutting-edge optical, electrophysiological, optogenetic, chemogenetic, electrochemical, anatomical, behavioral, and transcriptomic approaches. We propose three specific aims: 1) determine the mechanisms underlying cellular and network pathology in early-stage MCI-Park mice, where the motor impairment is modest; 2) determine the mechanisms underlying cellular and network pathology in late-stage MCI-Park mice that exhibit profound, levodopa-responsive motor deficits; 3) determine whether basal ganglia pathophysiology and motor deficits in late stage MCI-Park mice can be slowed or reversed. Execution of these aims should not only provide fundamental new insight into the mechanisms underlying the progression of PD but could also lead to novel therapeutic strategies for restoring function in symptomatic PD patients.
|Effective start/end date||4/15/21 → 3/31/26|
- National Institute of Neurological Disorders and Stroke (5R01NS121174-03)
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