Pioneering Rehabilitation

Brett C. Langley, Ph.D.

Director, Neuronal Epigenetics

Preclinical Traumatic Brain Injury Program

Associate Professor
Brain and Mind Research Institute
Weill Cornell Medicine


(914) 368-3142

Research Focus

My laboratory is focused on understanding the molecular events that determine a neuron’s fate following injury or during disease, and ultimately, whether they can be modulated therapeutically to promote better outcomes in patients. One strategy for promoting protection and/or regeneration in the nervous system is the inhibition of histone deacetylase (HDAC) enzymes by a class of compounds called HDAC inhibitors. These compounds inhibit the zinc hydrolase function of HDACs and allow the unopposed acetylation of histones, as well as certain transcription factors and cellular proteins. Acetylation of histone proteins within chromatin can enhance gene expression, while the acetylation of transcription factors and cellular proteins can modulate their protein-protein interaction and function.

Excitotoxicity, oxidative stress, and DNA damage are all well-established factors contributing to the degeneration of neurons during disease and injury. One line of investigation in my lab has been to define the mechanism by which HDAC inhibition protects neurons against DNA damage-induced death. We recently published that the neuroprotective efficacy of HDAC inhibitors can be attributed to their ability to modify the specific acetylation pattern of the tumour suppressor protein p53, which is a major regulator of pro-death gene expression during neurodegeneration (Brochier et. al., 2013). These observations have led us to explore the connection between HDAC activity and DNA repair in neurons. Unrepaired DNA damage can lead to cell death, whereas misrepaired damage increases the likelihood of mutagenesis, chromosome rearrangement, and loss of crucial genetic information. In replicating cells, such instability can result in apoptosis or cellular transformation. In the case of neurons residing in the adult brain, which are post-mitotic and terminally differentiated, and cannot be readily replaced after trauma or disease, the prospect of high fidelity repair would seem critical. Our efforts have revealed that in addition to protection from DNA damage-induced death, inhibiting HDAC activity also promotes durable DNA repair in post-mitotic neurons. Our current work explores the precise molecular mechanisms of this repair, both in vitro and in vivo.

Another line of investigation focuses on the prospect that HDAC inhibition in neurons may promote axonal repair. We have found that specifically inhibiting the function of HDAC6 in the axons of neurons can overcome the inhibitory effects of both myelin associated-glycoprotein and chondroitin sulfate proteoglycans, two molecules that impede axon regeneration after injury in the growth-hostile environment of a damaged spinal cord (Rivieccio et. al., 2009). Interestingly, the mechanism is independent of transcription, and involves HDAC6’s function as an α-tubulin deacetylase. We are currently investigating the regulation of HDAC6 following injury, its function and molecular targets in growth-inhibited axons, and the extent to which its activity can be inhibited to promote regeneration, both in vitro and in vivo. We model regeneration in vitro by culturing primary neurons with myelin associated-glycoprotein and/or chondroitin sulfate proteoglycans, while in vivo regeneration is studied in models of optic nerve crush injury (in retina-specific HDAC6 knockout mice) and thoracic contusion spinal cord injury (in pharmacologically HDAC6-inhibited rats).

In addition to HDAC inhibition, we are also interested in the potential for promoting protection and/or regeneration in the nervous system by increasing cellular levels of nicotinamide adenine dinucleotide (NAD+). NAD+ is an important energy substrate and cofactor involved in multiple metabolic reactions, including glycolysis, DNA repair processes, and the function of several NAD+-dependent enzymes, such poly (ADP-ribose) polymerases (PARPs) and sirtuins (a different class of histone deacetylase enzymes). These studies were established through collaboration with Drs Anthony Sauve and Samie Jaffrey in the Department of Pharmacology, and funded by the NY State SCIRB. Through these studies we have shown that by augmenting neuronal NAD+ via a NAD+ precursor, nicotinamide riboside, we can robustly protect neurons against DNA damage- and oxygen and glucose deprivation-induced death, and overcome the inhibitory effects of both myelin associated-glycoprotein and chondroitin sulfate proteoglycans, in vitro. Of immense importance to this project, the lab, and the collaboration, we have just completed thoracic contusion spinal cord injury studies in rats and find that nicotinamide riboside treatment can promote tissue sparing and greater functional recovery. We are continuing to investigate the roles of sirtuins and PARPs in promoting protection and axon growth (Brochier et al., 2015). We have also begun to explore the potential for nicotinamide riboside (as well as HDAC6 inhibition) in ameliorating peripheral neuropathy in a mouse model of Charcot Marie Tooth disease.


Brett Langley graduated with First Class Honors from the University of Waikato in New Zealand receiving his B.Sc. and M.Sc. In 2002 he received his Ph.D. (in Molecular Medicine) from the University of Auckland School of Medicine. Following his Ph.D. studies, Dr. Langley did postdoctoral research training under the mentorship of Prof. Rajiv R. Ratan at the Beth Israel Deaconess Medical Center and Harvard Medical School. Dr. Langley then joined the Faculty at the Burke Medical Research Institute and was appointed to the position of Instructor at the Brain Mind Research Institute at Weill Medical College of Cornell University. Presently, Dr. Langley remains at the Burke Medical Research Institute and is an Assistant Professor of the Brain Mind Research Institute at Weill Medical College of Cornell University.

Dr. Langley was the recipient of a Goldsmith Award in 2005, an Alzheimer’s Disease Drug Discovery Foundation (ADDF) Award in 2008, and is a current Adelson Medical Research Foundation (AMRF) Investigator in Neurorepair and Recovery (APNRR).

B.Sc. Biology
University of Waikato, New Zealand

M.Sc. Molecular Biology
University of Waikato, New Zealand

Ph.D. Molecular Medicine
University of Auckland, New Zealand

Postdoctoral Fellowship
Beth Israel Deaconess Medical Center, Boston
Harvard Medical School, Boston
Burke/Cornell Medical Research Institute, White Plains, New York
Goldsmith Fellowship Award

Weill Medical College of Cornell University, New York
Burke/Cornell Medical Research Institute, White Plains, New York

Associate Professor
Weill Medical College of Cornell University, New York
Burke/Cornell Medical Research Institute, White Plains, New York


Citations via PubMed

Journal Edited by John W. Cave, Brett Langley and Rajiv R. Ratan (2016) Epigenetics and Disorders of the Nervous System Neuroscience Letters. 2016 June 20, Volume 625, Pages 1-80

John W. Cave, Brett Langley, Rajiv R. Ratan (2016) Nature and nurture meet at the epigenome to modulate disorders of the nervous system Neuroscience Letters. 2016 June 20, Volume 625, Pages 1-3

Aleyasin H, Karuppagounder SS, Kumar A, Sleiman S, Basso M, Ma T, Siddiq A, Chinta SJ, Brochier C, Langley B, Haskew-Layton R, Bane SL, Riggins GJ, Gazaryan I, Starkov AA, Andersen JK, Ratan RR. 2014. Antihelminthic Benzimidazoles Are Novel HIF Activators That Prevent Oxidative Neuronal Death via Binding to Tubulin. Antioxid Redox Signal. 22(2):121-34

Ekins S, Litterman NK, Arnold RJ, Burgess RW, Freundlich JS, Gray SJ, Higgins JJ, Langley B, Willis DE, Notterpek L, Pleasure D, Sereda MW, Moore A. 2015. A brief review of recent Charcot-Marie-Tooth research and priorities. F1000Res. 4:53

Segretti M, Vallerini GP, Brochier C, Langley B, Wang L, Hancock W, Kozikowski A. 2015. Mercaptoacetamide Derivatives of 8-Aminoquinoline and 1,2,3,4-Tetrahydroquinoline are potent and selective histone deacetylase 6 (HDAC6) inhibitors and promote tubulin acetylation and T-regulatory cell suppressive function. ACS Medicinal Chemistry Letters. In Review, MS# ml-2015-00303q.

Brochier C, Jones JI, Willis DE, Langley B. Poly (ADP-ribose) polymerase 1 is a novel target to promote axonal regeneration. Proc Natl Acad Sci U S A. In Press, MS# 2015-09754.

Langley B, Sauve A.  2013.  Sirtuin deacetylases as therapeutic targets in the nervous systemNeurotherapeutics.  10(4):605-20.

Brochier C, Langley B.  2013.  Chromatin Modifications Associated with DNA Double-strand Breaks Repair as Potential Targets for Neurological DiseasesNeurotherapeutics.  10(4):817-30.

Brochier C, Dennis G, Rivieccio MA, McLaughlin K, Coppola G, Ratan RR, Langley B. 2013. Specific Acetylation of p53 by HDAC Inhibition Prevents DNA Damage-Induced Apoptosis in Neurons.  J Neurosci. 33(20):8621-32.

Ma TC, Langley B, Ko B, Wei N, Gazaryan IG, Zareen N, Yamashiro DJ, Willis DE, Ratan RR. 2012. A screen for inducers of p21(waf1/cip1) identifies HIF prolyl hydroxylase inhibitors as neuroprotective agents with antitumor properties. Neurobiol Dis. 49C:13-21.

Sleiman SF, Langley BC, Basso M, Berlin J, Xia L, Payappilly JB, Kharel MK, Guo H, Marsh JL, Thompson LM, Mahishi L, Ahuja P, MacLellan WR, Geschwind DH, Coppola G, Rohr J, Ratan RR. 2011. Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration. J Neurosci. 31(18):6858-70.

Haskew-Layton RE, Payappilly JB, Smirnova NA, Ma TC, Chan KK, Murphy TH, Guo H, Langley B, Sultana R, Butterfield DA, Santagata S, Alldred MJ, Gazaryan IG, Bell GW, Ginsberg SD, Ratan RR. Controlled enzymatic production of astrocytic hydrogen peroxide protects neurons from oxidative stress via an Nrf2-independent pathway.  Proc Natl Acad Sci U S A.  2010; 107(40):17385-90. 

McConoughey SJ, Basso M, Niatsetskaya ZV, Sleiman SF, Smirnova NA, Langley B, Mahishi L, Cooper AJ, Antonyak MA, Cerione RA, Li B, Starkov A, Chaturvedi RK, Beal MF, Coppola G, Geschwind DH, Ryu H, Xia L, Iismaa SE, Pallos J, Pasternack R, Hils M, Fan J, Raymond LA, Marsh JL, Thompson LM, Ratan RR. Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease.  EMBO Mol Med.  2010; 2(9):349-70

Butler KV, Kalin J, Brochier C, Vistoli G, Langley B, Kozikowski AP. Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A.  J Am Chem Soc.  2010; 132(31):10842-6

Akiba Y, Cave JW, Akiba N, Langley B, Ratan RR, Baker H. Histone deacetylase inhibitors de-repress tyrosine hydroxylase expression in the olfactory bulb and rostral migratory stream. Biochem Biophys Res Commun.  2010; 393(4):673-7.

Rivieccio MA, Brochier C, Willis DE, Walker BA, D'Annibale MA, McLaughlin K, Siddiq A, Kozikowski AP, Jaffrey SR, Twiss JL, Ratan RR, Langley B.  HDAC6 is a target for protection and regeneration following injury in the nervous system. Proc Natl Acad Sci U S A.  2009; 106(46):19599-604.

Butler, KV, He R, McLaughlin K, Vistoli G, Langley B, Kozikowski AP.  Stereoselective HDAC Inhibition from Cysteine-Derived Zinc-Binding Groups.  ChemMedChem.  2009; 4(8):1292-301. 

Langley B, Brochier C, Rivieccio M. Targeting histone deacetylases as a multifaceted approach to treat the diverse outcomes of stroke. Stroke.  2009; 40(8):2899-905.

Kozikowski AP, Chen Y, Subhasish T, Lewin NE, Blumberg PM, Zhong Z, D’Annibale MA, Wang W-L, Shen Y, Langley B.  Searching for disease modifiers – PKC activation and HDAC inhibition - A dual drug approach to Alzheimer’s disease that reduces Aβ production while blocking oxidative stress. ChemMedChem.  2009; 4(7):1095-105.

Sleiman SF, Basso M, Langley B, Mahishi L, Kozikowski AP, DonohoeME, Ratan R. Putting the “HAT” back on survival signaling: the promises and challenges of HDAC inhibitors in neurological therapeutics. Expert Opinion on Investigational Drugs. 2009; 18(5):573-84.

Chen Y, He R, Chen Y, D'Annibale MA, Langley B, Kozikowski AP.  Studies of benzamide- and thiol-based histone deacetylase inhibitors in models of oxidative-stress-Induced neuronal death: Identification of some HDAC3-selective inhibitors.  ChemMedChem.  2009; 4(5):842-52. 

Ratan RR, Siddiq A, Aminova L, Langley B, McConoughey S, Karpisheva K, Lee HH, Carmichael T, Kornblum H, Coppola G, Geschwind DH, Hoke A, Smirnova N, Rink C, Roy S, Sen C, Beattie MS, Hart RP, Grumet M, Sun D, Freeman RS, Semenza GL, Gazaryan I.  Small molecule activation of adaptive gene expression: tilorone or its analogs are novel potent activators of hypoxia inducible factor-1 that provide prophylaxis against stroke and spinal cord injury.  Ann N Y Acad Sci.  2008; 1147:383-94.

Jiang Y, Langley B, Lubin FD, Renthal W, Wood MA, Yasui DH, Kumar A, Nestler EJ, Akbarian S, Beckel-Mitchener AC.  Epigenetics in the nervous system. J Neuroscience. 2008; 28(46):11753-9

Langley B, D’Annibale MA, Suh K, Ayoub I, Bastan B, Yang L, Ko B, Fisher M, Beal MF, and Ratan RR. Pulse inhibition of HDACs induces complete resistance to oxidative death in cortical neurons without toxicity and reveals a role for cytoplasmic p21waf1/cip1 in cell cycle independent neuroprotection. J Neuroscience. 2008; 28(1):163-176.

Ratan RR, Siddiq A, Smirnova N, Karpisheva K, Haskew-Layton R, McConoughey S, Langley B, Estevez A, Huerta PT, Volpe B, Roy S, Sen CK, Gazaryan I, Cho S, Fink M, LaManna J.  Harnessing hypoxic adaptation to prevent, treat, and repair stroke. J Mol Med. 2007; 85(12):1331-8

Kozikowski AP, Chen Y, Gaysin A, Chen B, D'Annibale MA, Suto CM, and Langley B. Functional differences in epigenetic modulators - superiority of mercaptoacetamide based-HDAC inhibitors relative to hydroxamates in cortical neuron neuroprotection studies. J. Med. Chem. 2007; 50(13):3054-3061. 

McFarlane C, Langley B, Thomas M, Hennebry A, Plummer E, Nicholas G, McMahon C, Sharma M, Kambadur R.  Proteolytic processing of myostatin is auto-regulated during myogenesis.  Dev Biol. 2005; 283(1):58-69.

Camelo S, Iglesias AH, Hwang D, Due B, Ryu H, Smith K, Gray SG, Imitola J, Duran G, Assaf B, Langley B, Khoury SJ, Stephanopoulos G, De Girolami U, Ratan RR, Ferrante RJ, Dangond F.  Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. J Neuroimmunol. 2005; 164(1-2):10-21

Langley B, Gensert JM, Beal MF, Ratan RR. Remodeling chromatin and stress resistance in the central nervous system: histone deacetylase inhibitors as novel and broadly effective neuroprotective agents. Curr Drug Targets CNS Neurol Disord. 2005; 4(1):41-50.

Ferrante RJ, Ryu H, Kubilus JK, D'Mello S, Sugars KL, Lee J, Lu P, Smith K, Browne S, Beal MF, Kristal BS, Stavrovskaya IG, Hewett S, Rubinsztein DC, Langley Ratan RR. Chemotherapy for the brain: the antitumor antibiotic mithramycin prolongs survival in a mouse model of Huntington's disease. J Neuroscience.  2004; 24(46):10335-10342. 

Gardian G, Browne SE, Choi DK, Klivenyi P, Gregorio J, Kubilus JK, Ryu H, Langley B, Ratan RR, Ferrante RJ, Beal MF. Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington's disease. J Biol Chem.  2005; 280(1):556-563.

Ratan RR, Siddiq A, Aminova L, Lange PS, Langley B, Ayoub I, Gensert J, Chavez J.  Translation of ischemic preconditioning to the patient: prolyl Hydroxylase inhibition and hypoxia inducible factor-1 as novel targets for stroke therapy.  Stroke. 2004; 35(11 Suppl 1):2687-2689.

Lange PS, Langley B, Lu P, Ratan RR.  Novel roles for arginase in cell survival, regeneration, and translation in the central nervous system. J Nutr. 2004; 134(10 Suppl):2812S-2817S; discussion 2818S-2819S.

Langley B, Ratan RR.  Oxidative stress-induced death in the nervous system: cell cycle dependent or independent? J Neurosci Res. 2004; 77(5):621-629. 

Langley B, Thomas M, McFarlane C, Gilmour S, Sharma M, Kambadur R. Myostatin Inhibits Rhabdomyosarcoma Cell proliferation through an Rb-independent pathway. Oncogene. 2004; 23(2):524-534.

Langley B, Thomas M, Bishop A, Sharma M, Gilmour S, Kambadur R. Myostatin inhibits myoblast differentiation by down-regulating MyoD expression. J Biol Chem.  2002; 277(51):49831-49840. 

Nicholas G, Thomas M, Langley B, Somers W, Patel K, Kemp CF, Sharma M, Kambadur R. Titin-cap associates with, and regulates secretion of, myostatin. J Cell Physiol. 2002; 93(1):120-131.

Berry C, Thomas M, Langley B, Sharma M, Kambadur R. Single cysteine to tyrosine transition inactivates the growth inhibitory function of piedmontese myostatin. Am J Physiol Cell Physiol. 2002; 283(1):C135-141. 

Sharma M, Langley B, Bass J, Kambadur R.  Myostatin in muscle growth and repair.  Exerc Sport Sci Rev. 2001; 29(4):155-158.

Thomas M, Langley B, Berry C, Sharma M, Kirk S, Bass J, Kambadur R.  Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation. J Biol Chem. 2001; 22;275(51):40235-40243.

Prosser CG, Turner SA, McLaren RD, Langley B, L'Huillier PJ, Molan P, Auldist MJ.  Milk whey protein concentration and mRNA associated with beta-lactoglobulin phenotype. J Dairy Res. 2000; 67(2):287-293. 

Langley B, Vilotte JL, Stinnakre MG, Whitelaw CB, L'Huillier PJ.  Rescue of an MMTV transgene by co-integration reveals novel locus control properties of the ovine beta-lactoglobulin gene that confer locus commitment to heterogeneous tissues. Transgenic Res. 1998; 7(3):205-212.

Soulier S, Lepourry L, Stinnakre MG, Langley B, L'Huillier PJ, Paly J, Djiane J, Mercier JC, Vilotte JL. Introduction of a proximal Stat5 site in the murine alpha-lactalbumin promoter induces prolactin dependency in vitro and improves expression frequency in vivo. Transgenic Res. 1999; 8(1):23-31.


National Institutes of Health
National Institute of Neurological Disorders and Stroke. 1R01NS071056-01
Title: HDAC6: A Target for Regeneration Following Injury in the Nervous System.
Dates: 05/01/2011 – 04/30/2016
Roles: Co-Investigators - Brett Langley, Ph.D. and Caitlin Hill, Ph.D.

Adelson Medical Research Foundation (AMRF)
Adelson Program for Neurorepair and Recovery (APNRR) 
Title: Intrinsic mechanisms of axon degeneration and regeneration.
Dates: 10/01/2015 – 09/30/2017
Role: Principal Investigator - Brett Langley, Ph.D.

New York State Department of Health
Spinal Cord Injury Research Board
Title: Synthesis and Evaluation of NAD-augmenting Agents for Spinal Cord Injury
Role: Principal Investigator - Brett Langley, Ph.D.

Adelson Medical Research Foundation (AMRF)
Adelson Program for Neurorepair and Recovery (APNRR) 
Title: Specific Histone Deacetylase Isoforms as Targets for Neuroprotection and Repair in the Nervous System.
Principal Investigator - Brett Langley, Ph.D.


November 6, 2015
Dealing with Double Strand DNA Breaks in the Central Nervous System
Weill Medical College Brain Mind Research Institute Work in Progress Seminar Series

July 15-16, 2015
Targeting NAD: A strategy to treat traumatic brain injury
Big 10/CIC Ivy League Traumatic Brain Injury Summit

April 21, 2015
Invited Talk
Targeting HDACs for Neuroprotection and Repair
Drexel University, College of Arts and Sciences

November 6-7, 2014
Molecular Strategies to Prevent Peripheral Neuropathy in CMT2A
Hereditary Neuropathy Foundation Meeting


Current Lab Members:

Camille Brochier, Ph.D.

Victor Wong, Ph.D.
Postdoctoral Fellow

Cristina Picci, Ph.D.
Postdoctoral Fellow

Michelle Swift, B.S.