Martin Lab
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Ian Martin
Ph.D., Virginia Commonwealth University, 2008
Postdoctoral Fellow, Johns Hopkins University, 2009–2015
Faculty profile
martiia@ohsu.edu
503-494-9140
Ian received his B.S. degree from King's College, London and Ph.D. from Virginia Commonwealth University where he studied the impact of oxidative stress in determining life span and age-related functional declines in Drosophila. In 2009, he joined Ted and Valina Dawson's laboratory at Johns Hopkins University where he worked on molecular pathways underlying Parkinson's disease development linked to mutations in LRRK2 (leucine-rich repeat kinase 2). His work led to the discovery that mutant LRRK2 causes neurodegeneration through elevated bulk protein synthesis which is mediated by increased phosphorylation of the LRRK2 substrate ribosomal protein s15. In September 2015, Ian joined the Jungers Center as Associate Professor of Neurology with membership in the Parkinson Center of Oregon. Further Martin Lab information
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Research
Role of aging in neurodegeneration
The biggest risk factor for developing Parkinson’s disease (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 due to their elaborate neurite branching with consequent high metabolic demands and their intrinsic reactive oxygen species production through DA metabolism. While the case for macromolecular oxidative damage as a driver of cellular aging has recently been challenged, a growing body of evidence indicates that oxidative stress-responsive signaling may promote aging, although the molecular mediators are not well understood. We are actively investigating how oxidative stress-responsive signaling mediators that are important for lifespan determination intersect with neuronal health across age and, specifically, age-related maintenance of dopamine neuron viability.
Genetic susceptibility to neurotoxin-induced neurodegeneration
Epidemiological studies link pesticide exposure to Parkinson’s disease (PD) risk, yet human studies alone have not conclusively link PD etiology 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.
Mechanisms of LRRK2-mediated neurodegeneration in Parkinson’s disease
Genetic, aging, and environmental factors converge to establish a person’s lifetime risk of developing Parkinson’s disease (PD). A broad role for leucine-rich repeat kinase 2 (LRRK2) mutations in familial and idiopathic PD has emerged, elevating its status to a central therapeutic target. Ultimately, 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 performed a comprehensive screen for genetic modifiers of neurodegeneration in aged LRRK2 G2019S-expressing Drosophila, which exhibit robust age- and kinase-dependent loss of dopamine neurons (Lavoy et al., 2018). This approach identified a number of genes that regulate the morphology of neurites (axon and dendrites) which is striking considering that loss of neurite branch complexity is one of the most prevalent neuronal defects associated with pathogenic LRRK2 mutations in vitro. We are working with Drosophila and mammalian disease models to delineate the nature of these neurite defects in vivo, their underlying cause, and their relationship to dopamine neuron death.
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