# Determinants of Basal Ganglia Pathology in Parkinson's Disease

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $721,195

## Abstract

Summary
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.

## Key facts

- **NIH application ID:** 10182771
- **Project number:** 1R01NS121174-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Mark D Bevan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $721,195
- **Award type:** 1
- **Project period:** 2021-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10182771

## Citation

> US National Institutes of Health, RePORTER application 10182771, Determinants of Basal Ganglia Pathology in Parkinson's Disease (1R01NS121174-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10182771. Licensed CC0.

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