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.

Publications

View full list of publications on PubMed

Pallos, J., Jeng, S., McWeeney, S. and Martin, I. (2021) Dopamine Neuron-Specific LRRK2 G2019S Effects on Gene Expression Revealed by Translatome Profiling. Neurobiology of Disease, In Press.

Kim, J.K., Yin, X., Jhaldiyal, A., Kahn, M.R., Martin, I., Xie, Z., Perez-Rosello, T., Kumar, M., Abalde-Atristain, L., Xu, J., Chen, L., Eacker, S.M., Surmeier, S.M., Ingolia, N.T., Dawson, T.M. and Dawson, V.L. (2020). Defects in mRNA translation in LRRK2-mutant hiPSC-derived dopaminergic neurons leads to dysregulated calcium homeostasis. Cell Stem Cell, 27(4), 633-645.

Chittoor-Vinod, V.G., Villalobos-Cantor, S., Roshak, H., Shea, K., Abalde-Atristain, L. and Martin, I. (2020). Dietary Amino Acids Impact LRRK2-induced Neurodegeneration in Parkinson’s Disease Models. Journal of Neuroscience, 40(32), 6234-6249.

Lavoy, S., Chittoor-Vinod, V.G., Chow, C.Y. and Martin, I. (2018) Genetic Modifiers of Neurodegeneration in a Drosophila Model of Parkinson's Disease. Genetics, 209(4) 1345-1356.

Martin, I. (2017) Resveratrol for Alzheimer's disease? Science Translational Medicine 1;9(375) pii: eaam6055.

Kim, J.W., Abalde-Atristain, L., Jia, H., Martin, I., Dawson, V.L., Dawson, T.M. (2016) Protein translation in Parkinson’s disease. In: Verstreken P, eds. Parkinson’s Disease: Molecular Mechanisms Underlying Pathology. San Diego, CA: Elsevier.

Martin, I., Chittoor, V.G. (2016) Parkinson disease: Insect screens for PD therapies - keep the flies in. Nature Reviews Neurology, 12(6) 318-319. 

Martin, I. (2016) Decoding Parkinson’s Disease Pathogenesis: The Role of Deregulated mRNA Translation. Journal of Parkinson’s Disease, 6(1) 17-27.

Karuppagounder, S.S., Xiong, Y., Lee, Y., Lawless, M.C., Kim, D., Nordquist, E., Martin, I., Ge, P., Brahmachari, S., Jhaldiyal, A., Kumar, M., Andrabi, S.A., Dawson, T.M., Dawson, V.L. (2016) LRRK2 G2019S transgenic mice display increased susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated neurotoxicity. Journal of Chemical Neuroanatomy, 76(Pt B) 90-97.

Martin, I., Abalde-Atristain, L., Kim, J.W., Dawson, T., Dawson, V.L. (2014) Aberrant Protein Synthesis in G2019S LRRK2 Drosophila Parkinson's Disease-Related Phenotypes. Fly, 8(3) 165-169.

Martin, I., Kim, J.W., Lee, B.D., Kang, H., Xu, J-C., Jia, H., Stankowski, J., Kim, M-S., Zhong, J., Kumar, M., Andrabi, S.A., Xiong, Y., Dickson, D.W., Wszolek, Z.K., Pandey, A., Dawson, T.M., Dawson, V.L. (2014) Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. Cell, 157(2) 472-485.

Narayanasamy, S.K., Simpson, D.C., Martin, I., Grotewiel, M., Gronert, S. (2014) Paraquat exposure and Sod2 knockdown have dissimilar impacts on the Drosophila melanogaster carbonylated protein proteome. Proteomics, 14 (21) 2566-2577.

Martin, I., Dawson, V.L., Dawson, T.M. (2011) Recent advances in the genetics of Parkinson's disease. Annual Review of Genomics and Human Genetics, vol 22 p301-325.

Martin, I., Jones, M.A., Rhodenizer, D., Alaimo, J.T., Warrick, J.M., Seroude, L. and Grotewiel, M. (2009) Sod2 knock-down in the musculature has whole organism consequences in Drosophila. Free Radical Biology and Medicine 47(6) 803-813.

Martin, I., Jones, M.A. and Grotewiel M. (2009) Manipulation of Sod1 ubiquitously, but not in nervous system or muscle, impacts age-related parameters in Drosophila. FEBS Letters 583(13) 2308-2314.