Publications by authors named "Faith L Anderson"

6 Publications

  • Page 1 of 1

Lifestyle Factors and Parkinson's Disease Risk in a Rural New England Case-Control Study.

Parkinsons Dis 2021 2;2021:5541760. Epub 2021 Jul 2.

Geisel School of Medicine at Dartmouth, Rubin Building, Lebanon, NH, USA.

Introduction: Parkinson's disease (PD) is an age-related neurodegenerative disease likely caused by complex interactions between genetic and environmental risk factors. Exposure to pesticides, toxic metals, solvents, and history of traumatic brain injury have been implicated as environmental risk factors for PD, underscoring the importance of identifying risk factors associated with PD across different communities.

Methods: We conducted a questionnaire-based case-control study in a rural area on the New Hampshire/Vermont border, enrolling PD patients and age- and sex-matched controls from the general population between 2017 and 2020. We assessed frequent participation in a variety of recreational and occupational activities and surveyed potential chemical exposures.

Results: Suffering from "head trauma or a concussion" prior to diagnosis was associated with a fourfold increased risk of PD. Adjustment for head trauma negated any risk of participation in "strenuous athletic activities." We observed a 2.7-fold increased risk of PD associated with activities involving lead (adjusted =0.038).

Conclusion: Implicating these factors in PD risk favors public health efforts in exposure mitigation while also motivating future work mechanisms and intervention opportunities.
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http://dx.doi.org/10.1155/2021/5541760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270694PMC
July 2021

Bbc3 loss enhances survival and protein clearance in neurons exposed to the organophosphate pesticide chlorpyrifos.

Toxicol Sci 2021 Jul 21. Epub 2021 Jul 21.

Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH.

Exposure to environmental toxicants can increase the risk of developing age-related neurodegenerative disorders. Exposure to the widely used organophosphate pesticide chlorpyrifos (CPF) is associated with increased risk of developing Alzheimer's disease (AD) and Parkinson's disease (PD), but the cellular mechanisms underlying CPF toxicity in neurons are not completely understood. We evaluated CPF toxicity in mouse primary cortical neuronal cultures, using RNA-Seq to identify cellular pathways modulated by CPF. CPF exposure altered the expression of genes associated with intrinsic apoptosis, significantly elevating expression of the pro-apoptotic mediator Bbc3/Puma. Bbc3 loss attenuated CPF driven neurotoxicity, induction of other intrinsic apoptosis regulatory genes including Trp53 and Pmaip1 (encoding the NOXA protein), and cleavage of apoptosis executors caspase 3 and PARP. CPF exposure was associated with enhanced expression of ER stress-related genes and proteins and the accumulation of high molecular weight protein species in primary neuronal cultures. No evidence of alterations in the ubiquitin-proteosome system were observed, however, autophagy-related proteins were upregulated in CPF-treated Bbc3-/- neuronal cultures compared with identically exposed WT cultures. Elevated autophagy-related protein expression in Bbc3-/- neuronal cultures was associated with a reduction in CPF-induced high molecular weight alpha-synuclein and tau immunoreactive protein aggregates. Studies indicate that Bbc3-/- neuronal cultures enhance the ER stress response and upregulate protein clearance mechanisms as a component of resistance to CPF-mediated toxicity.
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http://dx.doi.org/10.1093/toxsci/kfab090DOI Listing
July 2021

Plasma-borne indicators of inflammasome activity in Parkinson's disease patients.

NPJ Parkinsons Dis 2021 Jan 4;7(1). Epub 2021 Jan 4.

Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms and loss of dopaminergic neurons of the substantia nigra. Inflammation and cell death are recognized aspects of PD suggesting that strategies to monitor and modify these processes may improve the management of the disease. Inflammasomes are pro-inflammatory intracellular pattern recognition complexes that couple these processes. The NLRP3 inflammasome responds to sterile triggers to initiate pro-inflammatory processes characterized by maturation of inflammatory cytokines, cytoplasmic membrane pore formation, vesicular shedding, and if unresolved, pyroptotic cell death. Histologic analysis of tissues from PD patients and individuals with nigral cell loss but no diagnosis of PD identified elevated expression of inflammasome-related proteins and activation-related "speck" formation in degenerating mesencephalic tissues compared with controls. Based on previous reports of circulating inflammasome proteins in patients suffering from heritable syndromes caused by hyper-activation of the NLRP3 inflammasome, we evaluated PD patient plasma for evidence of inflammasome activity. Multiple circulating inflammasome proteins were detected almost exclusively in extracellular vesicles indicative of ongoing inflammasome activation and pyroptosis. Analysis of plasma obtained from a multi-center cohort identified elevated plasma-borne NLRP3 associated with PD status. Our findings are consistent with others indicating inflammasome activity in neurodegenerative disorders. Findings suggest mesencephalic inflammasome protein expression as a histopathologic marker of early-stage nigral degeneration and suggest plasma-borne inflammasome-related proteins as a potentially useful class of biomarkers for patient stratification and the detection and monitoring of inflammation in PD.
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http://dx.doi.org/10.1038/s41531-020-00147-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782812PMC
January 2021

The effect of botulinum toxin on ureteral inflammation.

World J Urol 2021 Jun 21;39(6):2197-2204. Epub 2020 Jul 21.

Department of Urology, Dartmouth-Hitchcock, 1 Medical Center Dr, Lebanon, NH, USA.

Purpose: The impact of onabotulinum toxin type A (BoNT-A) on bladder afferent nerve pathways and chemosensory functions is an active area of investigation. There may be a role for BoNT-A in disorders of the ureter; however, no histologic studies have assessed the effects of BoNT-A on ureteral tissue. Our objective was to develop an animal model of ureteral inflammation and determine the impact of ureteral BoNT-A instillation on known mechanisms of inflammation.

Methods: The safety and feasibility of a novel animal model of ureteral inflammation was assessed. Through open cystotomy, the effect of ureteral BoNT-A instillation on inflammation was determined through H&E, masson's trichrome, Ki-67 stain, and prostaglandin E (PGE) synthase expression, a known marker of pain and inflammation in ureteral tissue. Urothelial microstructure was assessed using electron microscopy and standard histologic techniques.

Results: All experiments were carried to completion, and no systemic signs of botulinum toxicity were seen. BoNT-A exposure was associated with a decrease in PGE synthase expression in a dose-dependent fashion. BoNT-A exposure was not found to impact collagen deposition or cell proliferation. Disruption of tight junctions between urothelial cells was observed under conditions of inflammation.

Conclusion: We describe the feasibility of a novel in vivo model of ureteral inflammation and report the first histologic study of the effects of BoNT-A on the ureter. Preliminary findings show that BoNT-A attenuates ureteral PGE synthase expression under conditions of inflammation. The application of BoNT-A may provide anti-inflammatory and analgesic effects in the context of ureteral disorders.
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http://dx.doi.org/10.1007/s00345-020-03365-yDOI Listing
June 2021

Slc6a3-dependent expression of a CAPS-associated Nlrp3 allele results in progressive behavioral abnormalities and neuroinflammation in aging mice.

J Neuroinflammation 2020 Jul 17;17(1):213. Epub 2020 Jul 17.

Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, 1 Rope Ferry Road, Hanover, NH, 03755, USA.

Background: An association between neuroinflammation and age-related neurologic disorders has been established but the molecular mechanisms and cell types involved have not been thoroughly characterized. Activity of the proinflammatory NLRP3 inflammasome is implicated in Alzheimer's and Parkinson's disease and our recent studies in patients suggest that dopaminergic neurons within the degenerating mesencephalon express NLRP3 throughout the progression of PD. Here, we directly test the impact of enhanced inflammasome activity in mesencephalic neurons by characterizing motor function, tissue integrity, and neuroinflammation in aging mice harboring hyperactivating mutations within the endogenous murine Nlrp3 locus, enabled only in cells expressing the dopaminergic neuron-specific Slc6a3 promoter.

Methods: We compared mice harboring inducible alleles encoding the cryopyrin-associated periodic syndrome activating mutations Nlrp3 and Nlrp3 inserted into the endogenous mouse Nlrp3 locus. Tissue specific expression was driven by breeding these animals with mice expressing Cre recombinase under the control of the dopaminergic neuron-specific Slc6a3 promoter. The experimental mice, designed to express hyperactive NLRP3 only when the endogenous mouse Nlrp3 promotor is active in dopaminergic neurons, were analyzed throughout 18 months of aging using longitudinal motor function assessments. Biochemical and histologic analyses of mesencephalic tissues were conducted in 1- and 18-month-old animals.

Results: We observed progressive and significant deficits in motor function in animals expressing Nlrp3, compared with animals expressing Nlrp3 and Nlrp3. Age-dependent neuroinflammatory changes in the mesencephalon were noted in all animals. Analysis of GFAP-immunoreactive astrocytes in the substantia nigra revealed a significant increase in astrocyte number in animals expressing Nlrp3 compared with Nlrp3 and Nlrp3. Further analysis of Nlrp3 striatal tissues indicated genotype specific gliosis, elevated Il1b expression, and both morphologic and gene expression indicators of proinflammatory A1 astrocytes.

Conclusions: Dopaminergic neurons have the potential to accumulate NLRP3 inflammasome activators with age, including reactive oxygen species, dopamine metabolites, and misfolded proteins. Results indicate the Nlrp3 locus is active in dopaminergic neurons in aging mice, and that the hyperactive Nlrp3 allele can drive neuroinflammatory changes in association with progressive behavioral deficits. Findings suggest neuronal NLRP3 inflammasome activity may contribute to neuroinflammation observed during normal aging and the progression of neurologic disorders.
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http://dx.doi.org/10.1186/s12974-020-01866-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368774PMC
July 2020

Inflammasomes: An Emerging Mechanism Translating Environmental Toxicant Exposure Into Neuroinflammation in Parkinson's Disease.

Toxicol Sci 2018 11;166(1):3-15

Department of Molecular and Systems Biology.

Evidence indicates that complex gene-environment interactions underlie the incidence and progression of Parkinson's disease (PD). Neuroinflammation is a well-characterized feature of PD widely believed to exacerbate the neurodegenerative process. Environmental toxicants associated with PD, such as pesticides and heavy metals, can cause cellular damage and stress potentially triggering an inflammatory response. Toxicant exposure can cause stress and damage to cells by impairing mitochondrial function, deregulating lysosomal function, and enhancing the spread of misfolded proteins. These stress-associated mechanisms produce sterile triggers such as reactive oxygen species (ROS) along with a variety of proteinaceous insults that are well documented in PD. These associations provide a compelling rationale for analysis of sterile inflammatory mechanisms that may link environmental exposure to neuroinflammation and PD progression. Intracellular inflammasomes are cytosolic assemblies of proteins that contain pattern recognition receptors, and a growing body of evidence implicates the association between inflammasome activation and neurodegenerative disease. Characterization of how inflammasomes may function in PD is a high priority because the majority of PD cases are sporadic, supporting the widely held belief that environmental exposure is a major factor in disease initiation and progression. Inflammasomes may represent a common mechanism that helps to explain the strong association between exposure and PD by mechanistically linking environmental toxicant-driven cellular stress with neuroinflammation and ultimately cell death.
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http://dx.doi.org/10.1093/toxsci/kfy219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659017PMC
November 2018
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