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Our mission is to understand and prevent disorders of the brain


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Our mission is to understand and prevent disorders of the brain


Scroll down to learn more

Neurodegenerative disease is a growing storm at molecular, organismal and global scales. It represents one of the biggest health challenges of our time and will impact future generations with increasing force. We believe that basic scientific discovery will steer the course toward effective treatment and prevention of these disorders.

The Orr lab focuses on glial cells and mitochondria, which enable healthy brain function throughout life. Impairments in glia or mitochondria of the brain can initiate and promote brain damage and cognitive dysfunction in disease. We use multipronged experimental methods to unravel the complex interactions between different molecular pathways and cells in the brain. Our goal is to harness glial and mitochondrial signaling to prevent neurodegeneration and brain dysfunction in frontotemporal dementia, Alzheimer's disease and other devastating neurological disorders.

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Research Highlights


Research Highlights


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Leveraging Existing Therapeutics to Counteract Cognitive Deficits

New results show that short-term treatment with low doses of a selective receptor blocker enhances spatial memory in aging animals with chronic amyloid pathology, suggesting that existing drugs might counteract cognitive dysfunction in people with neurodegenerative disease.

 

Precise Blockade of Cell Damage Caused by Reactive Oxygen

Mitochondria produce ATP, but also generate reactive oxygen species implicated in disease-related cell damage. Newly discovered tools will help to precisely target reactive oxygen species without affecting the crucial process of ATP production.

Astrocytes Promote Forgetting in Health and Disease

'Star-shaped' glial cells are known to support neuronal health and function. New findings suggest that these cells may also be crucial for information storage and contribute to memory loss in disease. Therapeutically targeting these cells might prevent cognitive dysfunction in diverse disorders. 

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Meet Us


Meet Us


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Anna G. Orr, Ph.D.

Principal Investigator

 

Adam L. Orr, Ph.D.

Principal Investigator

 

Dr. Anna Orr earned her Ph.D. in Neuroscience from Emory University under the mentorship of Dr. Stephen Traynelis, where she studied the molecular mechanisms regulating microglial motility and neuroinflammation. She completed her postdoctoral training under the guidance of Dr. Lennart Mucke at the Gladstone Institute of Neurological Disease and UCSF, where she investigated the roles of astrocytic receptor signaling in cognitive function and Alzheimer’s disease. Dr. Orr has been honored with awards and grants from the Society for Neuroscience, NIA, NINDS, Alzheimer's Association, Leon Levy Foundation, and the Kellen Foundation.

Dr. Adam Orr received his Ph.D. in Neuroscience from Emory University under the guidance of Dr. Xiao-Jiang Li, where he studied mitochondrial transport in Huntington’s disease. He then trained with Dr. Martin Brand at the Buck Institute for Research on Aging where he explored mitochondrial reactive oxygen species production and discovered small molecules that selectively block this production. He has most recently worked at the Gladstone Institute of Neurological Disease in the labs of Drs. Ken Nakamura and Robert Mahley and in close collaboration with two start-up companies to therapeutically correct mitochondrial dysfunction in Parkinson’s and Alzheimer’s diseases.

 

Elsie C. Spencer, M.P.A.

Grants and Laboratory Administrator

Elsie Spencer received her Master's degree in Public Administration from Columbia University in 2007 and worked at Columbia University for 18 years prior to joining the Appel Institute of Weill Cornell Medicine. Her responsibilities include grants and laboratory administration and overall administrative matters relating to the Appel Institute.

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Avital Licht Murava, Ph.D.

Postdoctoral Fellow

Avital received her Ph.D. in Human Molecular Genetics and Biochemistry at the Sackler School of Medicine at Tel Aviv University under the mentorship of Dr. Hagit Eldar-Finkelman. Her thesis work led to the identification of a unique GSK-3 inhibitor, which reduced neuropathology and improved cognitive function in models of neurodegeneration. This work was featured as a “Signaling Breakthrough of the Year” by the journal Science Signaling. As a postdoc with Dr. Vahram Haroutunian at the Icahn School of Medicine, Avital focused on epigenetic RNA modifications (m6A) in the human brain and their association with aging and neurodegeneration. Avital was a recipient of the Sagol Fellowship and travel scholarships from scientific organizations. In the Orr lab, Avital is focusing on astrocytic signaling in health and disease.

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Samantha Meadows, B.S.

Neuroscience Graduate Student

Samantha Meadows received her Bachelor’s degree in Neuroscience from Binghamton University. During her undergraduate training, Samantha worked in Dr. Christopher Bishop's laboratory studying the neural mechanisms underlying L-DOPA-induced dyskinesia. Samantha was the recipient of Binghamton University's Summer Scholars and Artists Fellowship and the John L. Fuller Award for Excellence in Neuroscience Research. Samantha is currently interested in understanding how disruptions in astrocytic signaling contribute to the onset and progression of neurodegenerative and psychiatric illnesses. 

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Fernando Palaguachi, B.S.

Research Technician I

Fernando Palaguachi received his Bachelor’s degree in Neuroscience and Psychology from the City University of New York at Queens College. At Queens College, he worked as a Research Assistant in Dr. Joshua C. Brumberg’s neurocircuitry laboratory. Fernando's research focused on neuronal morphology and circuitry in the mouse barrel cortex. Because of his early academic and research achievements, Fernando was awarded the Raphell Sims Lakowitz Undergraduate Research Fellowship and was the first recipient of the Queens College Senior Class Legacy Scholarship. In the Orr lab, Fernando assists with diverse projects using animal models and culture methods to unravel the mechanisms of neurodegeneration and glial signaling.

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Svitlana Tymchuk, B.S.

Research Technician II

Svitlana Tymchuk graduated with honors from the Thomas Hunter Honors Program at Hunter College of the City University of New York, receiving a Bachelor's degree in Neurobiology and Interdisciplinary Studies with a minor in Psychology. After graduating, Svitlana worked as a research technician in the lab of Dr. Gregory A. Petsko at Weill Cornell, where she assisted with Alzheimer's disease research projects and engineering of novel fluorescent biosensors to study oxidative stress and neuroinflammation. Currently in the Orr lab, Svitlana is involved in various projects focusing on the roles of glial signaling in health and neurodegenerative disease. She has a keen curiosity and great passion for neuroscience research.

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Join Us


Join Us


We are looking for talented and motivated researchers who are passionate about neuroscience and mechanisms of neurological disease.

Our lab uses a variety of approaches and is seeking candidates with skills in molecular biology (CRISPR, RNAseq, cloning, etc), electrophysiology (preferably in vivo) and behavioral neuroscience. We welcome inquiries from graduate students and postdoctoral fellows interested in basic and translational neuroscience. Check out the links below to learn more about our research activities and lab culture. Our group is located in a new state-of-the-art research building in the vibrant upper east side of Manhattan and is part of the biomedical complex of Weill Cornell Medicine and NewYork-Presbyterian Hospital. If you are interested in joining our lab, please send your CV and a summary of previous work and current interests to ago2002@med.cornell.edu.  

 
 
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Find us


 

 

Find us


 

 

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Publications


Publications


2018

Plate-based measurement of superoxide and hydrogen peroxide production by isolated mitochondria.

Wong HS, Monternier PA, Orr AL, Brand MD. Methods in Molecular Biology http://www.ncbi.nlm.nih.gov/pubmed/29851006

Istradefylline reduces memory deficits in aging mice with plaque pathology.

Orr AG, Lo I, Schumacher H, Ho K, Gill M, Guo W, Kim DH, Knox A, Saito T, Saido TC, Simms J, Toddes C, Wang X, Yu GQ, Mucke L. Neurobiology of Disease *Featured on the journal cover.  http://www.ncbi.nlm.nih.gov/pubmed/29100987

2017

Loss of α-synuclein does not affect mitochondrial bioenergetics in rodent neurons.

Pathak D, Berthet A, Bendor J, Yu K, Sellnow R, Orr AL, Nguyen M, Edwards R, Manfredsson F, Nakamura K. eNeuro http://www.ncbi.nlm.nih.gov/pubmed/28462393

Long-term oral kinetin does not protect against α-synuclein-induced neurodegeneration in rodent models of Parkinson’s disease. 

Orr AL, Rutaganira FU, De Roulet D, Huang EJ, Hertz NT, Shokat KM, Nakamura K. Neurochem International http://www.ncbi.nlm.nih.gov/pubmed/28434973

2016

Suppressors of superoxide-H2O2 production at site Iq of mitochondrial complex I protect against stem cell hyperplasia and ischemia-reperfusion injury.

Brand MD, Goncalves RLS, Orr AL, Vargas L, Gerencser AA, Jensen MB, Wang YT, Melov S, Turk CN, Matzen JT, Dardov VJ, Petrassi HM, Meeusen SL, Perevoshchikova IV, Jasper H, Brookes PS, Ainscow EK. Cell Metabolism http://www.ncbi.nlm.nih.gov/pubmed/27667666

2015

Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory.

Orr AG, Hsiao EC, Wang MM, Ho K, Kim DH, Wang X, Guo W, Kang J, Yu GQ, Adame A, Devidze N, Dubal DB, Masliah E, Conklin BR, Mucke L. Nature Neuroscience http://www.ncbi.nlm.nih.gov/pubmed/25622143

Suppressors of superoxide production from mitochondrial complex III. 

Orr AL, Vargas L, Turk CN, Baaten JE, Matzen JT, Dardov VJ, Attle SJ, Li J,Quackenbush DC, Goncalves RLS, Perevoshchikova IV, Petrassi HM, Meeusen SL, Ainscow EK, Brand MD. Nature Chemical Biology  http://www.ncbi.nlm.nih.gov/pubmed/26368590

2014

Novel inhibitors of mitochondrial sn-glycerol 3-phosphate dehydrogenase.

Orr AL, Ashok D, Sarantos MR, Ng R, Shi T, Gerencser AA, Hughes RE, Brand MD. PLoS ONE http://www.ncbi.nlm.nih.gov/pubmed/24587137

Production of superoxide/H2O2 by dihydroorotate dehydrogenase in rat skeletal muscle mitochondria. 

Hey-Mogensen M, Goncalves RL, Orr AL, Brand MD. Free Radic Biol Med  http://www.ncbi.nlm.nih.gov/pubmed/24746616

2013

Inhibitors of ROS production by the ubiquinone-binding site of mitochondrial complex I identified by chemical screening. 

Orr AL, Ashok D, Sarantos MR, Shi T, Hughes RE, Brand MD. Free Rad Biol Med http://www.ncbi.nlm.nih.gov/pubmed/23994103

Sites of superoxide and hydrogen peroxide production during fatty acid oxidation in rat skeletal muscle mitochondria.

Perevoshchikova IV, Quinlan CL, Orr AL, Gerencser AA, Brand M. Free Rad Biol Med http://www.ncbi.nlm.nih.gov/pubmed/23583329

Sites of reactive oxygen species generation by mitochondria oxidizing different substrates. 

Quinlan CL, Perevoshchikova IV, Orr AL, Hey-Mogensen, M, Brand MD. Redox Biology http://www.ncbi.nlm.nih.gov/pubmed/24024165

NF-kB activity is inversely correlated to RNF11 expression in Parkinson's disease.

Pranski EL, Van Sanford CD, Dalal NV, Orr AL, Karmali D, Cooper DS, Gearing M, Lah JJ, Levey AI, Betarbet RS. Neuroscience Letters http://www.ncbi.nlm.nih.gov/pubmed/23669642

The role of mitochondrial function and cellular bioenergetics in aging and disease. 

Brand MD, Orr AL, Perevoshchikova IV, Quinlan CL. British Journal of Dermatology http://www.ncbi.nlm.nih.gov/pubmed/23786614

2012

Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model. 

Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop JJ, Mucke L. Proc Natl Acad Sci USA http://www.ncbi.nlm.nih.gov/pubmed/22869752

A refined analysis of superoxide production from mitochondrial sn-glycerol 3-phosphate dehydrogenase.

Orr AL, Quinlan CL, Perevoshchikova IV, Brand MD. Journal of Biological Chemistry http://www.ncbi.nlm.nih.gov/pubmed/23124204

Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions.

Quinlan CL, Orr AL, Perevoshchikova IV, Treberg JT, Brand MD. Journal of Biological Chemistry http://www.ncbi.nlm.nih.gov/pubmed/22689576

Neuronal RING finger protein 11 (RNF11) regulates canonical NF-κB signaling. 

Pranski EL, Dalal NV, Herskowitz JH, Orr AL, Roesch LA, Fritz JJ, Heilman C, Lah JJ, Levey AI, Betarbet RS. Journal of Neuroinflammation http://www.ncbi.nlm.nih.gov/pubmed/22507528

Comparative distribution of protein components of the A20 ubiquitin-editing complex in normal human brain.

Pranski EL, Van Sanford CD, Dalal NV, Orr AL, Karmali D, Cooper DS, Costa N, Heilman CJ, Gearing M, Lah JJ, Levey AI, Betarbet RS. Neuroscience Letters http://www.ncbi.nlm.nih.gov/pubmed/22634524

Native rates of superoxide production from multiple sites in isolated mitochondria measured using endogenous reporters

Quinlan CL, Treberg JT, Perevoshchikova IV, Orr AL, Brand MD. Free Rad Biol Med http://www.ncbi.nlm.nih.gov/pubmed/22940066

2011

Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. 

Cisse M, Halabisky B, Harris J, Devidze N, Dubal DB, Sun B, Orr AG, Lotz G, Kim DH, Hamto P, Ho K, Yu GQ, Mucke L. Nature http://www.ncbi.nlm.nih.gov/pubmed/21113149

A reduction in ATP demand and mitochondrial activity with neural differentiation of human embryonic stem cells. 

Birket MJ, Orr AL, Gerencser AA, Madden DT, Vitelli C, Swistowski A, Brand MD, Zeng X. Journal of Cell Science http://www.ncbi.nlm.nih.gov/pubmed/21242311

2010

Interleukin-1 mediates long-term hippocampal dentate granule cell loss following postnatal viral infection.

Orr AG, Sharma A, Binder NB, Miller AH, Pearce BD (2010) Journal of Molecular Neuroscience http://www.ncbi.nlm.nih.gov/pubmed/19774496

A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors. 

Mullasseril P, Hansen KB, Vance KM, Ogden KK, Yuan H, Kurtkaya NL, Santangelo R, Orr AG, Le P, Vellano KM, Liotta DC, Traynelis SF. Nature Communications http://www.ncbi.nlm.nih.gov/pubmed/20981015

Implementation of a fluorescence-based screening assay identifies histamine H3 receptor antagonists clobenpropit and iodophenpropit as subunit-selective N-methyl-D-aspartate receptor antagonists. 

Hansen KB, Mullasseril P, Dawit S, Kurtkaya NL, Yuan H, Vance KM, Orr AG, Kvist T, Ogden KK, Le P, Vellano KM, Lewis I, Kurtkaya S, Du Y, Qui M, Murphy TJ, Snyder JP, Bräuner-Osborne H, Traynelis SF. J Pharmacol Exp Ther http://www.ncbi.nlm.nih.gov/pubmed/20197375

Impaired mitochondrial trafficking in Huntington’s disease. 

Li XJ, Orr AL, Li S. Biochim Biophys Acta http://www.ncbi.nlm.nih.gov/pubmed/19591925

2009

Adenosine A2A receptor mediates microglial process retraction. 

Orr AG, Orr AL, Li XJ, Gross RE, Traynelis SF. Nature Neuroscience http://www.ncbi.nlm.nih.gov/pubmed/19525944

Differential regulation of microglial motility by ATP/ADP and adenosine. 

Gyoneva S, Orr AG, Traynelis SF. Parkinsonism Relat Disorders http://www.ncbi.nlm.nih.gov/pubmed/20082989

2008

N-terminal mutant htt associates with mitochondria directly and disrupts the interaction of mitochondria with trafficking proteins. 

Orr AL, Li SH, Wang CE, Li H, Wang J, Rong J, Xu X, Mastroberardino PG, Greenamyre JT, Li XJ. Journal of Neuroscience http://www.ncbi.nlm.nih.gov/pubmed/18337408

Sex-dependent effect of BAG-1 in ameliorating motor deficits of Huntington’s disease transgenic mice.

Orr AL, Huang S, Roberts MA, Fang ZH, Reed JC, Li SH, Li XJ. Journal of Biological Chemistry http://www.ncbi.nlm.nih.gov/pubmed/18400759

Plasmin potentiates synaptic N-methyl-D-aspartate receptor function in hippocampal neurons through activation of protease-activated receptor-1. 

Mannaioni G, Orr AG, Hamill CE, Yuan H, Pedone KH, McCoy KL, Berlinguer Palmini R, Junge CE, Lee CJ, Yepes M, Hepler JR, Traynelis SF. Journal of Biological Chemistry http://www.ncbi.nlm.nih.gov/pubmed/18474593

A FRET-based method to study protein thiol oxidation in histological preparations.

Mastroberardino PG, Orr AL, Hu X, Na HM, Greenamyre JT. Free Rad Biol Med http://www.ncbi.nlm.nih.gov/pubmed/18620047

Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington’s disease.

Wang CE, Tydlacka S, Orr A, Yang SH, Graham R, Hayden M, Li SH, Chan A, Li XJ. Human Molecular Genetics http://www.ncbi.nlm.nih.gov/pubmed/18558632

Impaired ubiquitin-proteasome system activity in the synapses of Huntington’s disease mice.

Wang J, Wang CE, Orr A, Tydlacka S, Li SH, Li XJ. Journal of Cell Biology http://www.ncbi.nlm.nih.gov/pubmed/18362179

2005

Activation of protease-activated receptor-1 triggers astrogliosis after brain injury. 

Nicole O, Goldshmidt A, Hamill CE, Sorensen SD, Sastre A, Lyuboslavsky P, Hepler JR, McKeon RJ, Traynelis SF. Journal of Neuroscience http://www.ncbi.nlm.nih.gov/pubmed/15858058

Glial reactivity after damage: implications for scar formation and neuronal recovery.

Hamill CE*, Goldshmidt A*, Nicole O, McKeon RJ, Brat DJ, Traynelis SF. Clinical Neurosurgery *Equal contributions. http://www.ncbi.nlm.nih.gov/pubmed/16626052

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Our Support


Our Support


We are grateful for our support and funding from

THE SWID FAMILY

and the following sources:

 
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