Scholars@Duke
Laurie H Sanders

Laurie H Sanders

Associate Professor in Neurology
Neurology, Movement Disorders
laurie.sanders@duke.edu
Box 103056, 3 Genome Court 5128 MSRB III, Durham, NC 27713
Box 103056, 3 Genome Court 5128 MSRB III, Durham, NC 27713

Selected Publications

G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage.

Journal Article NPJ Parkinsons Dis · March 1, 2024 Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. ... Full text Link to item Cite

Inactive S. aureus Cas9 downregulates alpha-synuclein and reduces mtDNA damage and oxidative stress levels in human stem cell model of Parkinson's disease.

Journal Article Sci Rep · October 18, 2023 Parkinson's disease (PD) is one of the most common neurodegenerative diseases, but no disease modifying therapies have been successful in clinical translation presenting a major unmet medical need. A promising target is alpha-synuclein or its aggregated fo ... Full text Link to item Cite

A blood-based marker of mitochondrial DNA damage in Parkinson's disease.

Journal Article Sci Transl Med · August 30, 2023 Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to en ... Full text Link to item Cite

α-synucleinopathy exerts sex-dimorphic effects on the multipurpose DNA repair/redox protein APE1 in mice and humans.

Journal Article Prog Neurobiol · September 2022 Lewy body disorders are characterized by oxidative damage to DNA and inclusions rich in aggregated forms of α-synuclein. Among other roles, apurinic/apyrimidinic endonuclease 1 (APE1) repairs oxidative DNA damage, and APE1 polymorphisms have been linked to ... Full text Link to item Cite

A Connection Between DNA Repair Protein APE1, Alpha-Synucleinopathy, and Biological Sex in Rodents and Humans

Journal Article FASEB journal : official publication of the Federation of American Societies for Experimental Biology · May 1, 2022 Lewy body disorders are characterized by proteostatic and redox disequilibrium, leading to deposition of α-synuclein in hallmark inclusions and oxidative damage to DNA. One common pathway for repair of oxidative DNA damage is base excision repair (BER), wh ... Full text Cite

Acoustofluidic multimodal diagnostic system for Alzheimer's disease.

Journal Article Biosens Bioelectron · January 15, 2022 Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative brain disorder that affects tens of millions of older adults worldwide and has significant economic and societal impacts. Despite its prevalence and severity, early diagnosis of A ... Full text Link to item Cite

DNA damage and repair in Parkinson's disease: Recent advances and new opportunities.

Journal Article J Neurosci Res · January 2021 Parkinson's disease (PD) is the most common movement neurodegenerative disorder. Although our understanding of the underlying mechanisms of pathogenesis in PD has greatly expanded, this knowledge thus far has failed to translate into disease-modifying ther ... Full text Link to item Cite

Somatic Mutations in LRRK2 Identify a Subset of Invasive Mammary Carcinomas Associated with High Mutation Burden.

Journal Article Am J Pathol · December 2020 Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkinson disease. Although LRRK2-related Parkinson disease patients have a heightened risk of certain nonskin cancers, including breast cancer, it is unknown ... Full text Link to item Cite

Mitochondrial DNA damage as a potential biomarker of LRRK2 kinase activity in LRRK2 Parkinson's disease.

Journal Article Sci Rep · October 14, 2020 Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for the treatment of Parkinson's disease (PD) and LRRK2 kinase inhibitors are currently being tested in early phase clinical trials. In order to ensure the highest chance of success, a ... Full text Link to item Cite

Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration.

Journal Article Nat Commun · November 19, 2018 While young muscle is capable of restoring the original architecture of damaged myofibers, aged muscle displays a markedly reduced regeneration. We show that expression of the "anti-aging" protein, α-Klotho, is up-regulated within young injured muscle as a ... Full text Link to item Cite

Evidence for Compartmentalized Axonal Mitochondrial Biogenesis: Mitochondrial DNA Replication Increases in Distal Axons As an Early Response to Parkinson's Disease-Relevant Stress.

Journal Article J Neurosci · August 22, 2018 Dysregulation of mitochondrial biogenesis is implicated in the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). However, it is not clear how mitochondrial biogenesis is regulated in neurons, with their unique compartmentalized a ... Full text Link to item Cite

LRRK2 activation in idiopathic Parkinson's disease.

Journal Article Sci Transl Med · July 25, 2018 Missense mutations in leucine-rich repeat kinase 2 (LRRK2) cause familial Parkinson's disease (PD). However, a potential role of wild-type LRRK2 in idiopathic PD (iPD) remains unclear. Here, we developed proximity ligation assays to assess Ser1292 phosphor ... Full text Link to item Cite

Newly Revised Quantitative PCR-Based Assay for Mitochondrial and Nuclear DNA Damage.

Journal Article Curr Protoc Toxicol · May 2018 Given the crucial role of DNA damage in human health and disease, it is important to be able to accurately measure both mitochondrial and nuclear DNA damage. This article describes a method based on a long-amplicon quantitative PCR-based assay that does no ... Full text Link to item Cite

DNA damage by oxidative stress: Measurement strategies for two genomes

Journal Article Current Opinion in Toxicology · February 1, 2018 DNA damage is any modification to the structure of DNA that alters its coding properties and/or interferes with cell processes. One major consequence of oxidative stress is DNA damage, which include base modifications, abasic sites, and strand breaks. A wi ... Full text Cite

RAD52 is required for RNA-templated recombination repair in post-mitotic neurons.

Journal Article J Biol Chem · January 26, 2018 It has been long assumed that post-mitotic neurons only utilize the error-prone non-homologous end-joining pathway to repair double-strand breaks (DSBs) associated with oxidative damage to DNA, given the inability of non-replicating neuronal DNA to utilize ... Full text Link to item Cite

Alpha-synuclein: Pathology, mitochondrial dysfunction and neuroinflammation in Parkinson's disease.

Journal Article Neurobiol Dis · January 2018 Parkinson's disease (PD) is a complex, chronic and progressive neurodegenerative disease. While the etiology of PD is likely multifactorial, the protein α-synuclein is a central component to the pathogenesis of the disease. However, the mechanism by which ... Full text Link to item Cite

LRRK2 G2019S-induced mitochondrial DNA damage is LRRK2 kinase dependent and inhibition restores mtDNA integrity in Parkinson's disease.

Journal Article Hum Mol Genet · November 15, 2017 Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with increased risk for developing Parkinson's disease (PD). Previously, we found that LRRK2 G2019S mutation carriers have increased mitochondrial DNA (mtDNA) damage and after zinc finger nuc ... Full text Link to item Cite

Synthetic alpha-synuclein fibrils cause mitochondrial impairment and selective dopamine neurodegeneration in part via iNOS-mediated nitric oxide production.

Journal Article Cell Mol Life Sci · August 2017 Intracellular accumulation of α-synuclein (α-syn) are hallmarks of synucleinopathies, including Parkinson's disease (PD). Exogenous addition of preformed α-syn fibrils (PFFs) into primary hippocampal neurons induced α-syn aggregation and accumulation. Like ... Full text Link to item Cite

Editor's Highlight: Base Excision Repair Variants and Pesticide Exposure Increase Parkinson's Disease Risk.

Journal Article Toxicol Sci · July 1, 2017 Exposure to certain pesticides induces oxidative stress and increases Parkinson's disease (PD) risk. Mitochondrial DNA (mtDNA) damage is found in dopaminergic neurons in idiopathic PD and following pesticide exposure in experimental models thereof. Base ex ... Full text Link to item Cite

Extensive uptake of α-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage.

Journal Article Mol Cell Neurosci · July 2017 The presence of Lewy bodies, mainly consisting of aggregated α-synuclein, is a pathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The α-synuclein inclusions are predominantly found in neurons, but also appear frequently ... Full text Link to item Cite

Toxin-Mediated Complex I Inhibition and Parkinson’s Disease

Chapter · October 13, 2016 Featured Publication This volume brings together various theories of how aberrations in mitochondrial function and morphology contribute to neurodegeneration in idiopathic and familial forms of Parkinson’s disease. ... Cite

Folding Landscape of Mutant Huntingtin Exon1: Diffusible Multimers, Oligomers and Fibrils, and No Detectable Monomer.

Journal Article PLoS One · 2016 Expansion of the polyglutamine (polyQ) track of the Huntingtin (HTT) protein above 36 is associated with a sharply enhanced risk of Huntington's disease (HD). Although there is general agreement that HTT toxicity resides primarily in N-terminal fragments s ... Full text Link to item Cite

LC/MS analysis of cardiolipins in substantia nigra and plasma of rotenone-treated rats: Implication for mitochondrial dysfunction in Parkinson's disease.

Journal Article Free Radic Res · May 2015 Exposure to rotenone in vivo results in selective degeneration of dopaminergic neurons and development of neuropathologic features of Parkinson's disease (PD). As rotenone acts as an inhibitor of mitochondrial respiratory complex I, we employed oxidative l ... Full text Link to item Cite

PCR based determination of mitochondrial DNA copy number in multiple species.

Journal Article Methods Mol Biol · 2015 Mitochondrial DNA (mtDNA) copy number is a critical component of overall mitochondrial health. In this chapter, we describe methods for isolation of both mtDNA and nuclear DNA (nucDNA) and measurement of their respective copy numbers using quantitative PCR ... Full text Link to item Cite

Mitochondrial DNA damage as a peripheral biomarker for mitochondrial toxin exposure in rats.

Journal Article Toxicol Sci · December 2014 Demonstrating or verifying a current or past exposure to an environmental mitochondrial toxin or toxicant is extraordinarily difficult. Thus, there is a pressing need to develop a biomarker for exposure to environmental mitochondrial inhibitors. Rotenone, ... Full text Link to item Cite

Mitochondrial DNA damage: molecular marker of vulnerable nigral neurons in Parkinson's disease.

Journal Article Neurobiol Dis · October 2014 DNA damage can cause (and result from) oxidative stress and mitochondrial impairment, both of which are implicated in the pathogenesis of Parkinson's disease (PD). We therefore examined the role of mitochondrial DNA (mtDNA) damage in human postmortem brain ... Full text Link to item Cite

LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: reversal by gene correction.

Journal Article Neurobiol Dis · February 2014 Parkinson's disease associated mutations in leucine rich repeat kinase 2 (LRRK2) impair mitochondrial function and increase the vulnerability of induced pluripotent stem cell (iPSC)-derived neural cells from patients to oxidative stress. Since mitochondria ... Full text Link to item Cite

Oxidative damage to macromolecules in human Parkinson disease and the rotenone model.

Journal Article Free Radic Biol Med · September 2013 Parkinson disease (PD), the most common neurodegenerative movement disorder, is associated with selective degeneration of nigrostriatal dopamine neurons. Although the underlying mechanisms contributing to neurodegeneration in PD seem to be multifactorial, ... Full text Link to item Cite

Overexpression of VMAT-2 and DT-diaphorase protects substantia nigra-derived cells against aminochrome neurotoxicity.

Journal Article Biochim Biophys Acta · July 2012 We tested the hypothesis that both VMAT-2 and DT-diaphorase are an important cellular defense against aminochrome-dependent neurotoxicity during dopamine oxidation. A cell line with VMAT-2 and DT-diaphorase over-expressed was created. The transfection of R ... Full text Link to item Cite

Regulation of complex I by Engrailed is complex too.

Journal Article Nat Neurosci · September 27, 2011 Full text Link to item Cite

Single-cell redox imaging demonstrates a distinctive response of dopaminergic neurons to oxidative insults.

Journal Article Antioxid Redox Signal · August 15, 2011 AIMS: The study of the intracellular oxido-reductive (redox) state is of extreme relevance to the dopamine (DA) neurons of the substantia nigra pars compacta. These cells possess a distinct physiology intrinsically associated with elevated reactive oxygen ... Full text Link to item Cite

Autophagy protects against aminochrome-induced cell death in substantia nigra-derived cell line.

Journal Article Toxicol Sci · June 2011 Aminochrome, the precursor of neuromelanin, has been proposed to be involved in the neurodegeneration neuromelanin-containing dopaminergic neurons in Parkinson's disease. We aimed to study the mechanism of aminochrome-dependent cell death in a cell line de ... Full text Link to item Cite

Epistatic roles for Pseudomonas aeruginosa MutS and DinB (DNA Pol IV) in coping with reactive oxygen species-induced DNA damage.

Journal Article PLoS One · April 18, 2011 Pseudomonas aeruginosa is especially adept at colonizing the airways of individuals afflicted with the autosomal recessive disease cystic fibrosis (CF). CF patients suffer from chronic airway inflammation, which contributes to lung deterioration. Once esta ... Full text Link to item Cite

The GO system prevents ROS-induced mutagenesis and killing in Pseudomonas aeruginosa.

Journal Article FEMS Microbiol Lett · May 2009 Inactivation of the Pseudomonas aeruginosa mutM, mutY, or mutT gene conferred a 2.4-, 17.2-, or 38.1-fold increase in spontaneous mutation frequency, respectively. Importantly, the mutY and mutT strains each displayed a robust H(2)O(2)-induced mutation fre ... Full text Link to item Cite

Sliding clamp-DNA interactions are required for viability and contribute to DNA polymerase management in Escherichia coli.

Journal Article J Mol Biol · March 20, 2009 Sliding clamp proteins topologically encircle DNA and play vital roles in coordinating the actions of various DNA replication, repair, and damage tolerance proteins. At least three distinct surfaces of the Escherichia coli beta clamp interact physically wi ... Full text Link to item Cite

Role of Escherichia coli DNA polymerase I in conferring viability upon the dnaN159 mutant strain.

Journal Article J Bacteriol · July 2007 The Escherichia coli dnaN159 allele encodes a mutant form of the beta-sliding clamp (beta159) that is impaired for interaction with the replicative DNA polymerase (Pol), Pol III. In addition, strains bearing the dnaN159 allele require functional Pol I for ... Full text Link to item Cite

Role of Pseudomonas aeruginosa dinB-encoded DNA polymerase IV in mutagenesis.

Journal Article J Bacteriol · December 2006 Pseudomonas aeruginosa is a human opportunistic pathogen that chronically infects the lungs of cystic fibrosis patients and is the leading cause of morbidity and mortality of people afflicted with this disease. A striking correlation between mutagenesis an ... Full text Link to item Cite