Laurie Sanders

Positions:

Assistant Professor in Neurology

Neurology, Movement Disorders
School of Medicine

Assistant Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Member in the Duke Clinical Research Institute

Duke Clinical Research Institute
School of Medicine

Education:

Ph.D. 2008

University at Buffalo, Jacobs School of Medicine and Biomedical Sciences

Postdoctoral Fellowship, Neurology/Pittsburgh Institute For Neurodegenerative Diseases

University of Pittsburgh

Institute For Clinical Research Education

University of Pittsburgh, School of Medicine

Grants:

Mechanisms of pathogenesis in LRRK2-related Parkinson's disease

Administered By
Neurology
Awarded By
William N. & Bernice E. Bumpus Foundation
Role
Principal Investigator
Start Date
End Date

Mitochondrial DNA damage in PD and control in a pesticide-exposed cohort

Administered By
Neurology
Awarded By
University of California - San Francisco
Role
Principal Investigator
Start Date
End Date

Mitochondrial DNA damage: screening tool and novel therapeutic target for Parkinson's disease

Administered By
Neurology
Awarded By
William N. & Bernice E. Bumpus Foundation
Role
Principal Investigator
Start Date
End Date

Mitochondrial DNA damage as a blood-based biomarker of early Parkinson's disease

Administered By
Neurology
Awarded By
Michael J. Fox Foundation for Parkinson's Research
Role
Principal Investigator
Start Date
End Date

Mitochondrial DNA damage in brain and blood in Alzheimer's disease

Administered By
Neurology
Awarded By
University of Pittsburgh
Role
Principal Investigator
Start Date
End Date

Publications:

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

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 biomarker-guided entry into clinical trials is key. LRRK2 phosphorylation, and phosphorylation of the LRRK2 substrate Rab10, have been proposed as target engagement biomarkers for LRRK2 kinase inhibition. However, a pharmacodynamic biomarker to demonstrate that a biological response has occurred is lacking. We previously discovered that the LRRK2 G2019S mutation causes mitochondrial DNA (mtDNA) damage and is LRRK2 kinase activity-dependent. Here, we have explored the possibility that measurement of mtDNA damage is a "surrogate" for LRRK2 kinase activity and consequently of kinase inhibitor activity. Mitochondrial DNA damage was robustly increased in PD patient-derived immune cells with LRRK2 G2019S mutations as compared with controls. Following treatment with multiple classes of LRRK2 kinase inhibitors, a full reversal of mtDNA damage to healthy control levels was observed and correlated with measures of LRRK2 dephosphorylation. Taken together, assessment of mtDNA damage levels may be a sensitive measure of altered kinase activity and provide an extended profile of LRRK2 kinase modulation in clinical studies.
Authors
Gonzalez-Hunt, CP; Thacker, EA; Toste, CM; Boularand, S; Deprets, S; Dubois, L; Sanders, LH
MLA Citation
Gonzalez-Hunt, C. P., et al. “Mitochondrial DNA damage as a potential biomarker of LRRK2 kinase activity in LRRK2 Parkinson's disease.Sci Rep, vol. 10, no. 1, Oct. 2020, p. 17293. Pubmed, doi:10.1038/s41598-020-74195-6.
URI
https://scholars.duke.edu/individual/pub1462859
PMID
33057100
Source
pubmed
Published In
Scientific Reports
Volume
10
Published Date
Start Page
17293
DOI
10.1038/s41598-020-74195-6

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

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 therapies. Therefore, it is of the utmost urgency to interrogate further the multifactorial etiology of PD. DNA repair defects cause many neurodegenerative diseases. An exciting new PD research avenue is the role that DNA damage and repair may play in neuronal death. The goal of this mini-review was to discuss the evidence for the types of DNA damage that accumulates in PD, which has provided clues for which DNA repair pathways, such as DNA double-strand break repair, are dysfunctional. We further highlight compelling data for activation of the DNA damage response in familial and idiopathic PD. The significance of DNA damage and repair is emerging in the PD field and linking these insights to PD pathogenesis may provide new insights into PD pathophysiology and consequently lead to new therapies.
Authors
Gonzalez-Hunt, CP; Sanders, LH
MLA Citation
Gonzalez-Hunt, Claudia P., and Laurie H. Sanders. “DNA damage and repair in Parkinson's disease: Recent advances and new opportunities.J Neurosci Res, vol. 99, no. 1, Jan. 2021, pp. 180–89. Pubmed, doi:10.1002/jnr.24592.
URI
https://scholars.duke.edu/individual/pub1431479
PMID
32048327
Source
pubmed
Published In
J Neurosci Res
Volume
99
Published Date
Start Page
180
End Page
189
DOI
10.1002/jnr.24592

Dopamine Metabolism May Have Unexpected Benefits for Mitochondrial Energy Production.

Authors
Sanders, LH; Calakos, N
MLA Citation
Sanders, Laurie H., and Nicole Calakos. “Dopamine Metabolism May Have Unexpected Benefits for Mitochondrial Energy Production.Mov Disord, vol. 35, no. 4, Apr. 2020, p. 562. Pubmed, doi:10.1002/mds.28005.
URI
https://scholars.duke.edu/individual/pub1433050
PMID
32073165
Source
pubmed
Published In
Mov Disord
Volume
35
Published Date
Start Page
562
DOI
10.1002/mds.28005

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

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. Likewise, intrastriatal inoculation of PFFs into mice and non-human primates generates Lewy bodies and Lewy neurites associated with PD-like neurodegeneration. Herein, we investigate the putative effects of synthetic human PFFs on cultured rat ventral midbrain dopamine (DA) neurons. A time- and dose-dependent accumulation of α-syn was observed following PFFs exposure that also underwent phosphorylation at serine 129. PFFs treatment decreased the expression levels of synaptic proteins, caused alterations in axonal transport-related proteins, and increased H2AX Ser139 phosphorylation. Mitochondrial impairment (including modulation of mitochondrial dynamics-associated protein content), enhanced oxidative stress, and an inflammatory response were also detected in our experimental paradigm. In attempt to unravel a potential molecular mechanism of PFFs neurotoxicity, the expression of inducible nitric oxide synthase was blocked; a significant decline in protein nitration levels and protection against PFFs-induced DA neuron death were observed. Combined exposure to PFFs and rotenone resulted in an additive toxicity. Strikingly, many of the harmful effects found were more prominent in DA rather than non-DA neurons, suggestive of higher susceptibility to degenerate. These findings provide new insights into the role of α-syn in the pathogenesis of PD and could represent a novel and valuable model to study DA-related neurodegeneration.
Authors
Tapias, V; Hu, X; Luk, KC; Sanders, LH; Lee, VM; Greenamyre, JT
MLA Citation
Tapias, Victor, et al. “Synthetic alpha-synuclein fibrils cause mitochondrial impairment and selective dopamine neurodegeneration in part via iNOS-mediated nitric oxide production.Cell Mol Life Sci, vol. 74, no. 15, Aug. 2017, pp. 2851–74. Pubmed, doi:10.1007/s00018-017-2541-x.
URI
https://scholars.duke.edu/individual/pub1259819
PMID
28534083
Source
pubmed
Published In
Cell Mol Life Sci
Volume
74
Published Date
Start Page
2851
End Page
2874
DOI
10.1007/s00018-017-2541-x

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

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 derived from rat substantia nigra. We found that aminochrome (50μM), in the presence of NAD(P)H-quinone oxidoreductase, EC 1.6.99.2 (DT)-diaphorase inhibitor dicoumarol (DIC) (100μM), induces significant cell death (62 ± 3%; p < 0.01), increase in caspase-3 activation (p < 0.001), release of cytochrome C, disruption of mitochondrial membrane potential (p < 0.01), damage of mitochondrial DNA, damage of mitochondria determined with transmission electron microscopy, a dramatic morphological change characterized as cell shrinkage, and significant increase in number of autophagic vacuoles. To determine the role of autophagy on aminochrome-induced cell death, we incubated the cells in the presence of vinblastine and rapamycin. Interestingly, 10μM vinblastine induces a 5.9-fold (p < 0.001) and twofold (p < 0.01) significant increase in cell death when the cells were incubated with 30μM aminochrome in the absence and presence of DIC, respectively, whereas 10μM rapamycin preincubated 24 h before addition of 50μM aminochrome in the absence and the presence of 100μM DIC induces a significant decrease (p < 0.001) in cell death. In conclusion, autophagy seems to be an important protective mechanism against two different aminochrome-induced cell deaths that initially showed apoptotic features. The cell death induced by aminochrome when DT-diaphorase is inhibited requires activation of mitochondrial pathway, whereas the cell death induced by aminochrome alone requires inhibition of autophagy-dependent degrading of damaged organelles and recycling through lysosomes.
Authors
Paris, I; Muñoz, P; Huenchuguala, S; Couve, E; Sanders, LH; Greenamyre, JT; Caviedes, P; Segura-Aguilar, J
MLA Citation
Paris, Irmgard, et al. “Autophagy protects against aminochrome-induced cell death in substantia nigra-derived cell line.Toxicol Sci, vol. 121, no. 2, June 2011, pp. 376–88. Pubmed, doi:10.1093/toxsci/kfr060.
URI
https://scholars.duke.edu/individual/pub1176166
PMID
21427056
Source
pubmed
Published In
Toxicological Sciences
Volume
121
Published Date
Start Page
376
End Page
388
DOI
10.1093/toxsci/kfr060