Central Nervous System (CNS) Biomarkers and Gene X Environment Interactions (GxE) In Neurodegenerative Diseases Research Group

The Central Nervous System (CNS) Biomarkers and Gene X Environment Interactions (GxE) In Neurodegenerative Diseases Research Group explores the environmental factors that may contribute to the development of adult-onset neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) by utilizing human biomarker and experimental model studies. This is a wet lab.

Ongoing Projects

Brain-Derived Extracellular Vesicles as Biomarkers in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a mostly sporadic and invariably fatal paralytic disorder. ALS pathogenic mechanisms are elusive, and its etiology is poorly understood, even if environmental exposures, including toxic metals, are thought to play a key role. Progresses in both therapy and prevention for ALS have been held back by the lack of clear biomarkers, indicative of patients’ disease progression and central nervous system (CNS) exposure to environmental toxicants. Here, we propose to test whether the cargoes of blood extracellular vesicles (EVs), i.e., tiny membrane-bound capsules that shuttle biomolecules out of the CNS, can serve as novel biomarkers of CNS metal exposure and disease progression in ALS. EVs carry nucleic acids (including microRNAs [miRNAs]), proteins, and other elements, while circulating throughout the body for interorgan communication. EVs also operate as ‘trash bags’ allowing cells to eliminate excesses of unwanted cellular materials, including toxic metals and proteins. CNS-EVs can be isolated from blood because they express on their surface the neuron-specific protein ATP1A3 or the astrocyte-specific protein GLAST. Blood CNS-EVs could open a direct window of observation into the ALS brain from the periphery and provide different types of biomarkers. First, CNS-EVs may reflect disease progression by carrying pathogenic proteins progressively accumulating in neurons and astrocytes in ALS, such as the TAR DNA-binding protein 43 (TDP-43), or by showing progressive changes in miRNA profiles. Second, CNS-EV metal levels could be a direct surrogate of CNS metal load, and as suggested by metals’ effects on miRNA profiles, they could provide a molecular fingerprint of patient metal exposure, when direct measurement is not possible. To test these hypotheses, we are currently leveraging unique biospecimen collections from well-phenotyped cohorts of ALS patients and a set of age- and sex-matched control samples. This work is a large interdisciplinary collaboration with epidemiologists, Drs. Marianthi-Anna Kioumourtzoglou, Pam Factor-Litvak and Ana Navas-Acien, analytical chemists, Drs, Beizhan Yan, Kathrin Schilling, Ronald Glabonjat, and Brian Jackson, and with clinicians Drs. Ikjae Lee, Elijah Stommel, Neil Shneider and Hiroshi Mitsumoto.

Novel Exposomics and EV Biomarkers to Unravel Gene-Environment Interactions and Mechanisms of Neurodegeneration in Parkinson's Disease

Parkinson’s disease (PD) is characterized by the progressive loss of neurons that produce a chemical messenger called “dopamine”, which is critical in the control of movement. Over the last decades, scientists have identified many genetic mutations in families affected by PD. But they represent only a small subset of patients, leaving 90% of the cases due to unknown causes; called “sporadic” or “idiopathic” PD. We do not know why these persons become sick; but because some occupations, such as working in the military, lead to a higher risk of developing PD, we believe they may have been exposed to substances or chemicals toxic for their brain. Metals, such as lead and manganese that are found in ammunitions, for instance, are among the prime candidates suspected to cause PD. Other toxic chemicals presumed to have a causal role in PD were found to contaminate military base drinking water systems. These toxic metals and chemicals are well known to accumulate in the brain over time. However, because PD does not develop in every person who is exposed to these toxic metals and chemicals, it is thought that the combination of individual vulnerability (e.g. a genetic pre-disposition) and toxic exposure can cause the disease. This is through a phenomenon called “gene-environment interaction.” Exposure to toxic metals and chemicals may not only have a role in “sporadic/idiopathic” PD but also in familial PD, as many people who carry a mutation causing PD in their family never develop the disease, known as incomplete penetrance. This is often the case for the mutations that we are currently studying in the gene LRRK2. Our central hypothesis is that exposure to, and brain accumulation of metals/organic toxicants, interacts with genetic mutations in LRRK2 to modulate the risk of developing PD. To test this hypothesis, we are currently combining investigations of environmental exposure in brain-derived EV biomarkers isolated from patient blood samples, on human dopamine neurons produced from patient skin cells by novel cell reprogramming technologies, and in “humanized” genetic mouse models of PD. In collaboration with the laboratory of Dr. Gary Miller at Columbia, our study is the first to evaluate exposomics in EVs.    Taken together, we anticipate that our studies will help elucidate the link(s) between exposure to metals/toxicants, the dysfunction of a key protein involved in PD, and the modulation of PD risk itself. We will validate novel EV biomarkers, which could become critical tools for PD diagnosis, but also in clinical trials to determine the benefit of new drugs. Ultimately, confirming the importance of toxicant-gene interactions in PD could promote the need for both environmental exposure and genetic counseling in PD prevention.

Electronic Cigarette Aerosol Neurotoxicity

Electronic cigarettes (e-cigs), battery-operated devices that heat liquids to generate an inhaled aerosol vapor, are increasingly popular, especially among younger users.  E-cigs are seen as an increasingly attractive alternative to tobacco cigarettes; however, little is known about the human health effects arising from chronic exposure to these aerosols. A growing number of studies have examined potential e-cig risks for cancer, respiratory, and cardiovascular diseases. New data from our laboratory and others, however, raise additional human health concerns about exposure to potentially neurotoxic metals released from the heated coil wire and other e-cig components. Our collaborators at Columbia, Drs. Hilpert, Kleiman and Navas-Acien, found that in a large fraction e-cig aerosol samples we collected, nickel, chromium, and lead levels exceeded EPA national ambient air quality standards or ATSDR minimum risk levels (MRL). Notably, this was true for manganese (Mn), a prime suspect in sporadic Parkinson’s disease (PD) etiology. Others have found that vanadium, copper and selenium (all suspected of a potential role in PD were higher in blood of e-cig users as compared to tobacco smokers. We hypothesize that hazardous metals released by e-cigs may accumulate in the brain and pose significant neurotoxic risk(s) for neurodegenerative diseases upon chronic exposure. Recently, we reported that mice exposed to e-cig aerosols for 60 days at relatively high environmental concentrations but low inhalation doses (2 hrs/day, 5 days/wk @ 800 mg/m3) showed significant increases of many metals, including Cu, Fe, Mn, Pb, and Sr in their striatum (a brain area key to both cognition and motricity, and affected early in PD), when compared to unexposed mice (Re et al., 2021). Other brain areas also showed metal accumulation and/or depletion of some essential metals such as Zn and Se. Thanks to a R01 from NIEHS, we are currently testing the reminder of our hypothesis in three ways. First, we are determining the levels of potentially neurotoxic metals in the aerosol produced by several popular e-cigs operated under different conditions and with e-liquids differing in flavor and nicotine content.  Second, we are examining the neurotoxic effect of chronic e-cig aerosol exposure in neuronal cell cultures derived from human subjects carrying incompletely penetrant mutations linked to PD or from healthy controls, and identify metal mixtures of particular neurotoxic concern. Third, we are measuring metal concentrations in brain tissue of chronically e-cig exposed mice, which are wildtype controls or knock-in for a mutation that increases the risk for PD; we are also determining the metals’ potential adverse effects on motor function and cognition in the mouse models. Findings from this study are likely to provide crucial and heretofore unavailable information to policy makers and will enable them to evaluate potential neurotoxic health risks arising from second-hand exposure to e-cig aerosol. We hypothesize that health risks are significantly influenced by genetic susceptibility to neurodegenerative disease, as well as by e-cig device construction, operating conditions, e-liquid flavoring, and nicotine content.  

Current Funding

R01 ES029971, NIH/NIEHS 01.02.20 – 01.31.25          
Re, Diane (PI)                                                                        
Brain-Derived Extracellular Vesicles as a Novel Source of Biomarkers for Disease Progression and Environmental Exposure in ALS

E01 W81XWH2210626, DOD Neurotoxin Exposure Treatment Parkinson 09.01.2022 – 08.31.2025                    
Re, Diane (PI)        
Novel exposomics and extracellular vesicle biomarkers to unravel gene-environment interactions and
mechanisms of neurodegeneration in Parkinson’s disease.

R01 ES032954, NIH/NIEHS 09.06.2021 – 09.05.2026                              
Re, Diane; Hilpert, Markus (MPI)                 
Neurotoxic and neurodegenerative risks from chronic exposure to metal mixtures in e-cigarette aerosol.

5P30ES009089-24, NIH/NIEHS 04.01.2023-05-31-2027
Re, Diane/Factor-Litvak, Pam (MPI)
Pilot Project Program
The goal of the Pilot Project Program (PPP) of the Center for Environmental Health and Justice in Northern Manhattan is to attract and retain junior and senior faculty in environmental health sciences, particularly those from backgrounds historically excluded from science and academia.

About Dr. Diane B. Ré

Diane B. Ré is an Associate Professor in the Department of Environmental Health Sciences at Columbia University. She is also the Co-Director of the Pilot Project Program at the NIEHS Center for Environmental Health and Justice of Northern Manhattan and a member of the Columbia Motor Neuron Center. Diane Ré received her Ph.D. in Neuroscience from the University of Aix-Marseille in the south of France. She completed her post-doctoral training in the Departments of Neurology and Pathology and Cell Biology at Columbia University, focusing on the adult-onset paralytic disorder Amyotrophic Lateral Sclerosis (ALS). Notably, her post-doctoral work pioneered the notion that in ALS neurons controlling voluntary movement are degenerating due to the transformation of supportive glial cells into hostile toxic neighbors. Now, Dr. Ré’s research effort is focusing on unraveling the contribution of environmental neurotoxic exposures and gene-environment interactions to the development of ALS and Parkinson’s disease (PD). Her current NIH and DOD funded research work concentrates on three aspects: 1) developing new in vitro and animal models of gene-metal/chemical interaction in ALS and PD; 2) isolating, characterizing, and validating novel neuronal and astroglial extracellular vesicle biomarkers of environmental exposure and disease progression in ALS and PD; 3) unraveling the neurotoxicity of electronic cigarette aerosol which represents a huge threat to youth brain health in our modern societies.

Diane Ré is a passionate teacher and mentor. She is the Director of the PI Crash Course: Skills for Future or New Lab Leaders.  This two-day intensive professional development training has already provided exposure to fundamental leadership, negotiation, staffing and management skills to several hundreds of junior Faculty and senior post-docs. She is also the Director of the "Fundamentals of Toxicology for Health-Related Disciplines" course that aims at introducing the basic concepts of toxicology to students from multiple health-related fields (epidemiologists, policy makers, etc.) who are interested in public health and the environmental basis of human disease. Diane Ré’s highest reward in her job is seeing her students and mentees growing as creative and rigorous scientists, well-rounded human beings, and future leaders in the fields of research or medicine. In her spare time, Diane loves hiking and skiing in the Poconos with her family and friends. She is the proud mom of two teenagers. She is also a food and wine enthusiast and a soccer fan.

You can find a list of select lab publications below, or view a complete list of Diane Ré's published work in her bibliography.