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Faculty

Pioneering Rehabilitation

Brett C. Langley, Ph.D.

Director, Neuronal Epigenetics

Assistant Professor, Neurology and Neuroscience

Weill Cornell Medical College

Phone:

(914) 368-3142

Research Focus

Our 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.

In collaboration with Dr. Ratan, one of our lines of investigation is to define the mechanism by which HDAC inhibition protects neurons against DNA damage-induced death. We are currently investigating the role of p53 in this death, the transcriptional targets that lie downstream of p53 activation, and how p53 is modulated by acetylation. 

Another line of investigation centers on the prospect that HDAC inhibition in neurons may promote 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 appears to be independent of transcription, and may involve HDAC6’s function as an a-tubulin deacetylase. We are currently investigating the function of HDAC6 in growth-inhibited axons and the extent to which its activity can be inhibited to promote regeneration, both in vitro and in vivo.

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) polymerase 1 (PARP1) and the surtuins (a different class of histone deacetylase enzymes).  Our findings are that augmenting neuronal NAD+ can protect neurons against DNA damage- and oxygen and glucose deprivation-induced death. We are currently investigating the mechanism of this protection.

Biography

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 of Neurology and Neuroscience at Weill Medical College of Cornell University. Presently, Dr. Langley remains at the Burke Medical Research Institute and is an Assistant Professor of Neurology and Neuroscience 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, N.Y.
Goldsmith Fellowship Award

Instructor
Weill Medical College of Cornell University, New York
Burke/Cornell Medical Research Institute, White Plains, N.Y.

 

Publications

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.

Funding

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.

New York State Department of Health
Spinal Cord Injury Research Board
Title: Synthesis and Evaluation of NAD-augmenting Agents for Spinal Cord Injury

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.

Laboratory

Current Lab Members:
Camille Brochier, Ph.D.  - Instructor
cab2026@med.cornell.edu 
Rebecca Meyer  - Technician
rem3002@med.cornell.edu
Mariajose Metcalfe, Ph.D.  - Postdoc
mam2139@med.cornell.edu
Mark Rivieccio, Ph.D.  - Postdoc
mar2057@med.cornell.edu
Jaime Tanner  - Technician