Laurie Sanders

Positions:

Assistant Professor in Neurology

Neurology, Movement Disorders
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2008

University at Buffalo State University of New York 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
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
Role
Principal Investigator
Start Date
End Date

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

Administered By
Neurology
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:

Toxin-mediated complex I inhibition and parkinson’s disease

© Springer International Publishing Switzerland 2016. Evidence of decreased mitochondrial complex I activity within the brain and peripheral tissues of idiopathic and familial forms of Parkinson’s disease (PD) implies an intrinsic vulnerability in the first complex of the electron transport chain (ETC). Several toxins of synthetic and natural origin have the ability to specifically inhibit complex I and reproduce parkinsonian-like features with remarkable similarity. Central to this mechanism is the selective vulnerability of the dopaminergic neurons of the substantia nigra (SN) and their axonal projections to the striatum (ST) to complex I inhibition. While no single etiological factor has been identified as the cause for the degeneration of dopamine neurons in sporadic PD, several lines of evidence suggest that loss of complex I activity is intimately related to the hallmark pathological features of the disease, including elevated levels of oxidative stress, neuroinflammation, and protein aggregation. The function of complex I and its production of reactive oxygen species following dysregulation are highlighted here, as well as the resulting neuropathology and its specific implications for the dopaminergic system.
Authors
De Miranda, BR; Van Houten, B; Sanders, LH
MLA Citation
De Miranda, B. R., et al. “Toxin-mediated complex I inhibition and parkinson’s disease.” Mitochondrial Mechanisms of Degeneration and Repair in Parkinson’s Disease, 2016, pp. 115–37. Scopus, doi:10.1007/978-3-319-42139-1_6.
URI
https://scholars.duke.edu/individual/pub1176449
Source
scopus
Published Date
Start Page
115
End Page
137
DOI
10.1007/978-3-319-42139-1_6

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

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 with the DNA that it topologically encircles. We utilized mutant beta clamp proteins bearing G66E and G174A substitutions (beta159), affecting the single-stranded DNA-binding region, or poly-Ala substitutions in place of residues 148-HQDVR-152 (beta(148-152)), affecting the double-stranded DNA binding region, to determine the biological relevance of clamp-DNA interactions. As part of this work, we solved the X-ray crystal structure of beta(148-152), which verified that the poly-Ala substitutions failed to significantly alter the tertiary structure of the clamp. Based on functional assays, both beta159 and beta(148-152) were impaired for loading and retention on a linear primed DNA in vitro. In the case of beta(148-152), this defect was not due to altered interactions with the DnaX clamp loader, but rather was the result of impaired beta(148-152)-DNA interactions. Once loaded, beta(148-152) was proficient for DNA polymerase III (Pol III) replication in vitro. In contrast, beta(148-152) was severely impaired for Pol II and Pol IV replication and was similarly impaired for direct physical interactions with these Pols. Despite its ability to support Pol III replication in vitro, beta(148-152) was unable to support viability of E. coli. Nevertheless, physiological levels of beta(148-152) expressed from a plasmid efficiently complemented the temperature-sensitive growth phenotype of a strain expressing beta159 (dnaN159), provided that Pol II and Pol IV were inactivated. Although this strain was impaired for Pol V-dependent mutagenesis, inactivation of Pol II and Pol IV restored the Pol V mutator phenotype. Taken together, these results support a model in which a sophisticated combination of competitive clamp-DNA, clamp-partner, and partner-DNA interactions serve to manage the actions of the different E. coli Pols in vivo.
Authors
Heltzel, JMH; Scouten Ponticelli, SK; Sanders, LH; Duzen, JM; Cody, V; Pace, J; Snell, EH; Sutton, MD
MLA Citation
Heltzel, Justin M. H., et al. “Sliding clamp-DNA interactions are required for viability and contribute to DNA polymerase management in Escherichia coli..” J Mol Biol, vol. 387, no. 1, Mar. 2009, pp. 74–91. Pubmed, doi:10.1016/j.jmb.2009.01.050.
URI
https://scholars.duke.edu/individual/pub1176172
PMID
19361435
Source
pubmed
Published In
J Mol Biol
Volume
387
Published Date
Start Page
74
End Page
91
DOI
10.1016/j.jmb.2009.01.050

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

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 such as the HTT exon1 protein, there is no consensus on the nature of the physical states of HTT exon1 that are induced by polyQ expansion, nor on which of these states might be responsible for toxicity. One hypothesis is that polyQ expansion induces an alternative, toxic conformation in the HTT exon1 monomer. Alternative hypotheses posit that the toxic species is one of several possible aggregated states. Defining the nature of the toxic species is particularly challenging because of facile interconversion between physical states as well as challenges to identifying these states, especially in vivo. Here we describe the use of fluorescence correlation spectroscopy (FCS) to characterize the detailed time and repeat length dependent self-association of HTT exon1-like fragments both with chemically synthesized peptides in vitro and with cell-produced proteins in extracts and in living cells. We find that, in vitro, mutant HTT exon1 peptides engage in polyQ repeat length dependent dimer and tetramer formation, followed by time dependent formation of diffusible spherical and fibrillar oligomers and finally by larger, sedimentable amyloid fibrils. For expanded polyQ HTT exon1 expressed in PC12 cells, monomers are absent, with tetramers being the smallest molecular form detected, followed in the incubation time course by small, diffusible aggregates at 6-9 hours and larger, sedimentable aggregates that begin to build up at 12 hrs. In these cell cultures, significant nuclear DNA damage appears by 6 hours, followed at later times by caspase 3 induction, mitochondrial dysfunction, and cell death. Our data thus defines limits on the sizes and concentrations of different physical states of HTT exon1 along the reaction profile in the context of emerging cellular distress. The data provide some new candidates for the toxic species and some new reservations about more well-established candidates. Compared to other known markers of HTT toxicity, nuclear DNA damage appears to be a relatively early pathological event.
Authors
Sahoo, B; Arduini, I; Drombosky, KW; Kodali, R; Sanders, LH; Greenamyre, JT; Wetzel, R
MLA Citation
Sahoo, Bankanidhi, et al. “Folding Landscape of Mutant Huntingtin Exon1: Diffusible Multimers, Oligomers and Fibrils, and No Detectable Monomer..” Plos One, vol. 11, no. 6, Jan. 2016. Epmc, doi:10.1371/journal.pone.0155747.
URI
https://scholars.duke.edu/individual/pub1176157
PMID
27271685
Source
epmc
Published In
Plos One
Volume
11
Published Date
Start Page
e0155747
DOI
10.1371/journal.pone.0155747

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

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 viability. We have utilized a combination of genetic and biochemical approaches to characterize the role(s) played by Pol I in the dnaN159 strain. Our findings indicate that elevated levels of Pol I partially suppress the temperature-sensitive growth phenotype of the dnaN159 strain. In addition, we demonstrate that the beta clamp stimulates the processivity of Pol I in vitro and that beta159 is impaired for this activity. The reduced ability of beta159 to stimulate Pol I in vitro correlates with our finding that single-stranded DNA (ssDNA) gap repair is impaired in the dnaN159 strain. Taken together, these results suggest that (i) the beta clamp-Pol I interaction may be important for proper Pol I function in vivo and (ii) in the absence of Pol I, ssDNA gaps may persist in the dnaN159 strain, leading to lethality of the dnaN159 DeltapolA strain.
Authors
Maul, RW; Sanders, LH; Lim, JB; Benitez, R; Sutton, MD
MLA Citation
Maul, Robert W., et al. “Role of Escherichia coli DNA polymerase I in conferring viability upon the dnaN159 mutant strain..” Journal of Bacteriology, vol. 189, no. 13, July 2007, pp. 4688–95. Epmc, doi:10.1128/JB.00476-07.
URI
https://scholars.duke.edu/individual/pub1176168
PMID
17449610
Source
epmc
Published In
Journal of Bacteriology
Volume
189
Published Date
Start Page
4688
End Page
4695
DOI
10.1128/JB.00476-07

Fruit flies, bile acids, and Parkinson disease: a mitochondrial connection?

Authors
Greenamyre, JT; Sanders, LH; Gasser, T
MLA Citation
Greenamyre, J. Timothy, et al. “Fruit flies, bile acids, and Parkinson disease: a mitochondrial connection?.” Neurology, vol. 85, no. 10, Sept. 2015, pp. 838–39. Pubmed, doi:10.1212/WNL.0000000000001912.
URI
https://scholars.duke.edu/individual/pub1176158
PMID
26253445
Source
pubmed
Published In
Neurology
Volume
85
Published Date
Start Page
838
End Page
839
DOI
10.1212/WNL.0000000000001912