The Sanders lab studies Parkinson’s disease (PD), the most common neurodegenerative movement disorder. Even with expert treatment, PD patients typically deteriorate over time and endure considerable motor and non-motor disability. There are no disease modifying therapies, thus, this is an urgent unmet medical need. We take a translational approach (i.e. bench-to-bedside), aiming to translate our multidisciplinary basic scientific research into meaningful health outcomes for PD patients. To do so, we combine all levels of analysis, from neurons in a dish to human studies. We have adapted, developed, and are continuing to create and apply novel methods and technology for PD mechanistic investigation. Our primary focus is on the role of genome integrity and DNA repair in the pathogenesis of PD.

We were the first to show that LRRK2 G2019S mutation carriers have increased mitochondrial DNA (mtDNA) damage using human induced pluripotent stem cells (iPSC)-derived neural cells (Sanders et al 2014). Further, the mtDNA damage phenotype was shown to be caused by the LRRK2 mutations. When the mutations were “corrected” using zinc finger nuclease (ZFN)-mediated gene editing, levels of mtDNA damage returned to that of basal control levels. Thus, the mtDNA damage phenotype can be unambiguously attributed to the LRRK2 G2019S mutation. This new link between LRRK2 and mtDNA damage opens up an entirely original line of investigation into the pathogenic mechanisms of LRRK2-related PD. Our current work focuses on the underlying mechanisms of LRRK2-induced mtDNA damage, dysfunction and neurodegeneration.

We also found selective mtDNA damage as a molecular marker of vulnerable nigral neurons in sporadic PD. We are able to detect mitochondrial abasic sites (with brain region and cell type specificity) in multiple pre-clinical models of PD and in human PD postmortem brain tissue (Sanders et al 2014). We are interested in pursuing the underlying DNA repair defect in PD and applying novel therapeutic approaches targeting genome integrity.

There are no peripheral biomarkers for PD. The identification and validation of high throughput biomarkers to measure disease progression (as well as identify pre-clinical disease onset) is critical to the development of disease-modifying or even preventative therapies. We are investigating and defining peripheral biomarkers for PD.

• Hao N, Wang Z, Liu P, Becker R, Yang S, Yang K, Pei Z, Zhang P, Xia J, Shen L, Wang L, Welsh-Bohmer KA, Sanders L, Lee LP, Huang TJ. Acoustofluidic multimodal diagnostic system for Alzheimer's disease. Biosens Bioelectron. 2021 Oct 29;196:113730. doi: 10.1016/j.bios.2021.113730. Epub ahead of print. PMID: 34736099.
• Kakar RS, Pastor JV, Moe OW, Ambrosio F, Castaldi D, Sanders LH. Peripheral Klotho and Parkinson's Disease. Mov Disord. 2021 Feb 25. doi: 10.1002/mds.28530. Epub ahead of print. PMID: 33629770.
• Gonzalez-Hunt CP, Sanders LH. DNA damage and repair in Parkinson's disease: Recent advances and new opportunities. J Neurosci Res. 2021 Jan;99(1):180-189. doi: 10.1002/jnr.24592. Epub 2020 Feb 12. PMID: 32048327.
• Parrilla Castellar ER, Plichta JK, Davis R, Gonzalez-Hunt C, Sanders LH. Somatic Mutations in LRRK2 Identify a Subset of Invasive Mammary Carcinomas Associated with High Mutation Burden. Am J Pathol. 2020 Dec;190(12):2478-2482. doi: 10.1016/j.ajpath.2020.08.010. Epub 2020 Sep 12. PMID: 32931768.
• Gonzalez-Hunt CP, Thacker EA, Toste CM, Boularand S, Deprets S, Dubois L, Sanders LH. Mitochondrial DNA damage as a potential biomarker of LRRK2 kinase activity in LRRK2 Parkinson's disease. Sci Rep. 2020 Oct 14;10(1):17293. doi: 10.1038/s41598-020-74195-6. PMID: 33057100; PMCID: PMC7557909.
• Sanders LH, Calakos N. Dopamine Metabolism May Have Unexpected Benefits for Mitochondrial Energy Production. Mov Disord. 2020 Apr;35(4):562. doi: 10.1002/mds.28005. Epub 2020 Feb 19. PMID: 32073165.
• Sahu, A, Mamiya, H, Shinde, SN, Cheikhi, A, Winter, LL., Vo, NV, Stolz, D, Roginskaya, V, Tang, WY, St Croix, C., Sanders, LH, Franti, M, Van Houten, B, Rando, TA, Barchowsky, A, … Ambrosio, F (2018). "Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration." Nature communications, 9(1), 4859. doi:10.1038/s41467-018-07253-3.
• Di Maio R, Hoffman EK, Rocha EM, Keeney MT, Sanders LH, De Miranda BR, Zharikov A, Van Laar A, Stepan AF, Lanz TA, Kofler JK, Burton EA, Alessi DR, Hastings TG, Greenamyre JT. "LRRK2 activation in idiopathic Parkinson's disease." Sci Transl Med. 2018 Jul 25;10(451). pii: eaar5429. doi: 10.1126/scitranslmed.aar5429.
• Sanders LH, Rouanet JP, Howlett EH, Leuthner TC, Rooney JP, Greenamyre JT, Meyer JN. "Newly Revised Quantitative PCR-Based Assay for Mitochondrial and Nuclear DNA Damage." Curr Protoc Toxicol. 2018 May;76(1):e50. doi: 10.1002/cptx.50.
• Van Laar VS, Arnold B, Howlett EH, Calderon MJ, St Croix CM, Greenamyre JT, Sanders LH, Berman SB. "Evidence for Compartmentalized Axonal Mitochondrial Biogenesis: Mitochondrial DNA Replication Increases in Distal Axons As an Early Response to Parkinson's Disease-Relevant Stress." J Neurosci. 2018 Aug 22;38(34):7505-7515. Epub 2018 Jul 20
• Welty, S, Teng, Y, Liang, Z, Zhao, W, Sanders, LH, Greenamyre, JT, Rubio, ME, Thathiah, A, Kodali, R, Wetzel, R, Levine, AS, and Lan, L. "RAD52 is required for RNA-templated recombination repair in post-mitotic neurons." Journal of Biological Chemistry 293, no. 4 (January 1, 2018): 1353-1362.
• Gonzalez-Hunt, CP, Wadhwa, M, and Sanders, LH. "DNA damage by oxidative stress: Measurement strategies for two genomes." Current Opinion in Toxicology 7 (February 1, 2018): 87-94. (Review).
• Howlett E, Jensen N, Belmonte F et al. LRRK2 G2019S-induced mitochondrial DNA damage is LRRK2 kinase dependent and inhibition restores mtDNA integrity in Parkinson’s disease. Human Molecular Genetics. 2017;26(22):4340-4351. doi:10.1093/hmg/ddx320.
• Tapias, V, Hu, X, Luk, KC, Sanders, LH, Lee, VM, and Greenamyre, JT. "Synthetic alpha-synuclein fibrils cause mitochondrial impairment and selective dopamine neurodegeneration in part via iNOS-mediated nitric oxide production (Published online)." Cellular and Molecular Life Sciences 74, no. 15 (August 2017): 2851-2874. 
• Lindström, V, Gustafsson, G, Sanders, LH, Howlett, EH, Sigvardson, J, Kasrayan, A, Ingelsson, M, Bergström, J, and Erlandsson, A. "Extensive uptake of α-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage." Molecular and Cellular Neuroscience 82 (July 2017): 143-156. 
• Sanders, LH, Paul, KC, Howlett, EH, Lawal, H, Boppana, S, Bronstein, JM, Ritz, B, and Greenamyre, JT. "Editor’s Highlight: Base Excision Repair Variants and Pesticide Exposure Increase Parkinson’s Disease Risk." Toxicological Sciences 158, no. 1 (July 2017): 188-198. 
• Rocha, EM, De Miranda, B, and Sanders, LH. "Alpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease." Neurobiology of Disease (April 2017). 
• Sahoo, B, Arduini, I, Drombosky, KW, Kodali, R, Sanders, LH, Greenamyre, JT, and Wetzel, R. "Folding Landscape of Mutant Huntingtin Exon1: Diffusible Multimers, Oligomers and Fibrils, and No Detectable Monomer." Edited by DR Borchelt. PLOS ONE 11, no. 6 (June 6, 2016): e0155747-e0155747. 
• Greenamyre, JT, Sanders, LH, and Gasser, T. "Fruit flies, bile acids, and Parkinson disease: a mitochondrial connection?" Neurology 85, no. 10 (September 2015): 838-839. 
• Tyurina, YY, Polimova, AM, Maciel, E, Tyurin, VA, Kapralova, VI, Winnica, DE, Vikulina, AS, Domingues, MRM, McCoy, J, Sanders, LH, Bayır, H, Greenamyre, JT, and Kagan, VE. "LC/MS analysis of cardiolipins in substantia nigra and plasma of rotenone-treated rats: Implication for mitochondrial dysfunction in Parkinson's disease." Free radical research 49, no. 5 (May 2015): 681-691. 
• Sanders, LH, Howlett, EH, McCoy, J, and Greenamyre, JT. "Mitochondrial DNA damage as a peripheral biomarker for mitochondrial toxin exposure in rats." Toxicological sciences : an official journal of the Society of Toxicology 142, no. 2 (December 2014): 395-402. 
• Rooney, JP, Ryde, IT, Sanders, LH, Howlett, EH, Colton, MD, Germ, KE, Mayer, GD, Greenamyre, JT, and Meyer, JN. "PCR based determination of mitochondrial DNA copy number in multiple species." (October 11, 2014): 23-38. (Chapter) 
• Sanders, LH, McCoy, J, Hu, X, Mastroberardino, PG, Dickinson, BC, Chang, CJ, Chu, CT, Van Houten, B, and Greenamyre, JT. "Mitochondrial DNA damage: molecular marker of vulnerable nigral neurons in Parkinson's disease." Neurobiology of disease 70 (October 2014): 214-223. 
• Sanders, LH, Laganière, J, Cooper, O, Mak, SK, Vu, BJ, Huang, YA, Paschon, DE, Vangipuram, M, Sundararajan, R, Urnov, FD, Langston, JW, Gregory, PD, Zhang, HS, Greenamyre, JT, Isacson, O, and Schüle, B. "LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: reversal by gene correction." Neurobiology of disease 62 (February 2014): 381-386. 
• Sanders, LH, and Greenamyre, JT. "Oxidative damage to macromolecules in human Parkinson disease and the rotenone model." Free radical biology & medicine 62 (September 2013): 111-120. (Review) 
• Muñoz, P, Paris, I, Sanders, LH, Greenamyre, JT, and Segura-Aguilar, J. "Overexpression of VMAT-2 and DT-diaphorase protects substantia nigra-derived cells against aminochrome neurotoxicity." Biochimica et biophysica acta 1822, no. 7 (July 2012): 1125-1136. 
• Sanders, LH, and Greenamyre, JT. "Regulation of complex I by Engrailed is complex too." Nature neuroscience 14, no. 10 (October 2011): 1221-1222. 
• Horowitz, MP, Milanese, C, Di Maio, R, Hu, X, Montero, LM, Sanders, LH, Tapias, V, Sepe, S, van Cappellen, WA, Burton, EA, Greenamyre, JT, and Mastroberardino, PG. "Single-cell redox imaging demonstrates a distinctive response of dopaminergic neurons to oxidative insults." Antioxidants & redox signaling 15, no. 4 (August 2011): 855-871. 
• Paris, I, Muñoz, P, Huenchuguala, S, Couve, E, Sanders, LH, Greenamyre, JT, Caviedes, P, and Segura-Aguilar, J. "Autophagy protects against aminochrome-induced cell death in substantia nigra-derived cell line." Toxicological sciences : an official journal of the Society of Toxicology 121, no. 2 (June 2011): 376-388. 
• Sanders, LH, Devadoss, B, Raja, GV, O'Connor, J, Su, S, Wozniak, DJ, Hassett, DJ, Berdis, AJ, and Sutton, MD. "Epistatic roles for Pseudomonas aeruginosa MutS and DinB (DNA Pol IV) in coping with reactive oxygen species-induced DNA damage." PloS one 6, no. 4 (April 18, 2011): e18824-. 
• Sanders, LH, Sudhakaran, J, and Sutton, MD. "The GO system prevents ROS-induced mutagenesis and killing in Pseudomonas aeruginosa." FEMS microbiology letters 294, no. 1 (May 2009): 89-96. 
• Heltzel, JMH, Scouten Ponticelli, SK, Sanders, LH, Duzen, JM, Cody, V, Pace, J, Snell, EH, and Sutton, MD. "Sliding clamp-DNA interactions are required for viability and contribute to DNA polymerase management in Escherichia coli." Journal of molecular biology 387, no. 1 (March 2009): 74-91. 
• Maul, RW, Sanders, LH, Lim, JB, Benitez, R, and Sutton, MD. "Role of Escherichia coli DNA polymerase I in conferring viability upon the dnaN159 mutant strain." Journal of bacteriology 189, no. 13 (July 2007): 4688-4695. 
• Sanders, LH, Rockel, A, Lu, H, Wozniak, DJ, and Sutton, MD. "Role of Pseudomonas aeruginosa dinB-encoded DNA polymerase IV in mutagenesis." Journal of bacteriology 188, no. 24 (December 2006): 8573-8585. 
• Sanders, LH. "Phenotype of the zebrafish masterblind (mbl) mutant is dependent on genetic background." Developmental Dynamics 227, no. 2 (2003): 291-300.

The Sanders group is always looking for interested, talented members for our team. Please email Dr Sanders at laurie.sanders@duke.edu to learn more about open positions.