Piecing Together the Parkinson’s Puzzle

The movement disorder in Parkinson's disease (PD) is caused by a loss of dopamine neurons from the substantia nigra. PD is a complex multifactorial disease with roots in genetics, aging and the environment. Work in the Martin laboratory focuses on three main areas of investigation:

1. Genetic mutations that result in PD and provide important clues into the molecular basis of disease development 
2. Genetic susceptibility to environmental toxins linked to PD
3. Identifying mechanisms of biological aging that impact dopamine neuron health and vulnerability to loss in PD pathogenesis.

For each area, we use a combination of Drosophila and rodent animal models and a wealth of biochemical, advanced imaging, -omics and behavioral approaches.

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Single Single GFP-labeled dopamine neuron showing axon terminal arborization. Maximum projection image through the posterior Drosophila brain following confocal microscopy.

 

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LRRK2 in Parkinson's Disease

Mutations in LRRK2 (leucine-rich repeat kinase 2) are commonly found in both familial and sporadic PD. Preventing LRRK2-induced neurodegeneration will require a detailed understanding of the key mechanisms driving neuronal dysfunction and death. LRRK2 has been implicated in numerous biological processes, but defining mechanisms that drive age-related neuronal death has been elusive. We recently performed a comprehensive screen to identify genes that influence age-dependent loss of dopamine neurons in LRRK2 G2019S-expressing Drosophila. This approach yielded a number of genes that regulate the morphology of neurites (axon and dendrites). Our current work, in collaboration with investigators at the Van Andel Institute, is aimed at delineating the nature of mutant LRRK2-induced neurite defects in vivo, their underlying cause and their relationship to dopamine neuron death.

Role of Aging in Neurodegeneration

The biggest risk factor for developing PD is age, suggesting that age-related changes in the brain predispose to loss of dopamine (DA) neuron health and viability. Cell stressors such as oxidative stress and metabolic dysfunction increase with age, and DA neurons are particularly vulnerable to this stress. A growing body of evidence indicates that oxidative stress-responsive signaling may promote aging, although the molecular mediators are not well understood. In collaboration with groups at the University of Washington, we are actively investigating how oxidative stress-responsive signaling mediators important for lifespan regulation intersect with neuronal health across age, particularly age-related maintenance of dopamine neuron viability. ​​

Confocal images of dopamine neurons from the brains of aged flies belonging to either short-lived strains that lose dopamine neurons with age or long-lived that retain dopamine neurons with age, mean lifespans ± SEM annotated. Image reproduced from Coleman et al., PNAS 2024.

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Genetic Susceptibility to Neurotoxins in PD

Epidemiological studies link pesticide exposure to PD risk, yet human studies alone have not conclusively linked PD to any single pesticide. Controlled animal models play a vital role in determining whether pesticides can cause PD-related neurodegeneration and can be leveraged to gain mechanistic insight into disease etiology. We are using Drosophila to identify genes underlying susceptibility to neurotoxins such as pesticides that have been linked to PD. Genes identified through this approach will then be pursued in rodent models of neurodegeneration in order to assess their potential contribution to disease development.