Department of Molecular and Cell Biology

School of Natural Sciences and Mathematics

Faculty and Research

Santosh D'Mello, PhD

Santosh R D'Mello
RL 1.708

faculty profile


B.S., University of Bombay
M.S., University of Bombay
Ph.D., University of Pittsburgh
Postdoctoral Training, Boston University Medical School
Postdoctoral Training, Institute of Neurobiology, Rome


Research in the lab is centered on understanding the molecular mechanisms regulating neurodegeneration.  Specifically, primary cultures of neurons, transgenic and knockout mice, and animal models of neurological disease are used to study genes, proteins, and signal transduction pathways regulating neuronal cell death.  We are also interested in identifying chemical compounds that protect the brain from neurodegeneration. The long-term objective of the laboratory’s research is to develop strategies to prevent, treat, or cure degenerative diseases of the brain.  Recently, we have expanded our interests to investigate neurodevelopmental disorders also. 

Research interests

Our ongoing research on neurodegeneration and neurodevelopmental disorders is described below.

Neurodegenerative disorders
Neurodegenerative diseases such as AD, PD and HD are progressive and fatal disorders affect millions of individuals in the U.S. alone costing the economy over $100 billion annually.   While there are drugs that can reduce the symptoms associated with some of these diseases (for example, Parkinson’s disease), these do not slow down the relentless loss of neurons and therefore the disease progresses.  Our lab is interested in understanding the molecular mechanisms underlying neurodegeneration.  We hope that our efforts will lead to the identification of molecules that are important in the control of neuronal survival and death and whose altered function contributes to neurodegenerative disorders.  Such molecules can then be targeted in the development of effective therapeutic strategies for these disorders.  Much of our focus has been on histone deacetylases (HDACs) a family of 18 proteins initially identified based on their ability to repress gene expression through the deacetylation of histones, but which are now known to have a variety of other functions mediated through the deacteylation of non-histone proteins residing in the nucleus, cytoplasm or mitochondria.  Chemical inhibitors of HDACs protect neurons from death in animal models of neurodegenerative diseases.  Because the chemical inhibitors used so far inhibit all HDAC proteins, however, the identity of the specific HDAC(s) responsible for promoting neurodegeneration has remained unclear.  We recently discovered that activation of HDAC3 has a neurotoxic effect and hence this protein is the likely target of the HDAC inhibitors in their neuroprotective effect.  In ongoing studies funded by the NIH, we are investigating the role of HDAC3 in the pathogenesis of Huntington’s disease.  Surprisingly, while HDAC3 can be neurotoxic, we have found that some of the other HDAC proteins, including HDAC4, HDAC7, and HDAC9, promote the survival of neurons and protect them form degenerative stimuli. 
            Another protein of interest to the lab is FoxG1, a transcription factor that is critical for proper brain development where it controls the production of neurons by regulating proliferation of neural progenitor cells.  Mice that lack FoxG1 have a severely underdeveloped brain and die early during gestation. But FoxG1 is highly expressed in the adult brain where its function had not been studied.  We recently found that FoxG1 maintains the survival of mature neurons. We have been investigating the molecular mechanism through which the activity of FoxG1 is regulated and the mechanism by which FoxG1 affects other molecules to maintain the survival of neurons.  As part of an NIH-funded project, we are currently generating transgenic mice that express elevated levels of FoxG1.  These mice will be used to test whether elevated FoxG1 can protect mice against neurodegenerative diseases such as Huntington’s disease.  Among other proteins that are being currently studied in the lab are the transcription factors c-Fos, FoxP1, HSF1 and Jaz, the chaperone protein DNAJB6, and a protein that resides in the nucleolus called nucleophosmin-1.
            In addition to understanding the molecular biology of neurodegeneration the lab has been identifying chemical compounds that protect neurons from death.  This drug discovery effort has led to the identification of several indolone and benzoxazine compounds that are highly protective in cell culture models and animal models of neurodegenerative diseases.  Exactly how these neuroprotective compounds act is an area of interest.  Some of the benzoxazine compounds have been licensed to EnCephRx, a biotechnology company dedicated to finding a treatment for Huntington’s disease.

Neurodevelopmental disorders
Several years ago we reported the identification of a novel rat mutant that displayed abnormal brain development.  This mutant, which we called Flathead, was microcephalic (small brain), suffered severe seizures, and had progressive ataxia and paralysis of the hindlimbs.  We found that the neurological abnormalities in Flathead were caused by the death of late developing neural progenitor cells which resulted from a defect in cytokinesis.  We discovered that the mutation in Flathead is in the gene encoding a protein called citron kinase which regulates cyokinesis.
            Recently, we have been interested in MeCP2, a gene that can repress gene transcription globally as well as locally.  Mutations in the MeCP2 gene cause Rett syndrome, a neurodevelopmental disorder characterized by normal early growth and development followed by a slowing of development, loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, problems with walking, seizures, and intellectual disability.  While reduced MeCP2 activity causes Rett syndrome, elevated activity of this protein as a result of duplication or triplication of the MeCP2 gene causes a disorder called MeCP2 duplication syndrome.  Patients with this disorder are born normal but then display progressive mental retardation, spasticity, epilepsy, and die at adulthood.  We are studying MeCP2 duplication syndrome using transgenic mice that make 3-4 times more MeCP2 than normal.  Like patients, these mice display neurological deficiencies and die early in adulthood.  We find that MeCP2 transgenic mice display neuronal loss in certain brain regions just before they die.  We are characterizing other abnormalities in the MeCP2 transgenic brain with the goal of getting a better understanding of why human patients with MeCP2 duplication syndrome suffer the neurological phenotype that they do.  A recent discovery that we have made is that astrocytes within certain brain regions of the MeCP2 transgenic mice have high levels of a protein called GFAP.  Interestingly, increased GFAP production is the primary cause of another neurological brain disorder called Alexander disease, which is characterized by spasticity, mental retardation, and seizures.  We are exploring whether MeCP2 duplication syndrome and Alexander disease share mechanistic commonalities.

Recent publications (Last 5 years only)
Chen H-M, Wang L, D’Mello SR.  (2008) Inhibition of ATF-3 expression by B-Raf mediates the neuroprotective action of GW5074.J. Neurochem. 105:1300-1132

Zhang X, Jaramillo E, Wang L, D’Mello SR. (2008) Histone deacetylase-related protein inhibits AES-mediated neuronal cell death by direct interaction J. Neurosci. Res. 86:2423-2431. (Cover article)

Majdzadeh N, Morrison BE, Wang L, D’Mello SR. (2008) HDAC4 inhibits cell cycle progression and protects neurons from cell death. Dev. Neurobiol. 68:1076-1092

Morrison BE and D’Mello SR. (2008) Polydactyly in mice lacking HDAC9/HDRP.  Experimental Biology and Medicine 233:980-988.

Chen HM, Wang L, D'Mello SR. (2008) A chemical compound commonly used to inhibit PKR, {8-(imidazol-4-ylmethylene)-6H-azolidino[5,4-g] benzothiazol-7-one}, protects neurons by inhibiting cyclin-dependent kinase. Eur J Neurosci. 28:2003-2016.

Balderamos M, Ankati H, Akubathini SK, Patel AV, Kamila S, Mukherjee C, Wang L, Biehl ER, D'Mello SR. (2008) Synthesis and Structure-Activity Relationship Studies of 3-Substituted Indolin-2-ones as Effective Neuroprotective Agents. Exp Biol Med 233:1395-1402.

Pfister JA, Ma C, Morrison BE, D’Mello SR. (2008) Opposing effects of sirtuins on neuronal survival: SIRT1-mediated neuroprotection is independent of its deacetylase activity. PLos One 3(12):e4090.

Ankanti H, Akubathini SK, Kamila S, Mukherjee C, D’Mello SR, Biehl ER (2008).  Synthesis of 3-benzylidene, 5-substituted 3-bennzylidene, 3-hetarylmethylene and 5-substituted hetarylmethylene derivatives of indolin-2-ones.  Organic Chemistry Journal 2: 138-147.

Wang L, Ankati H, Akubathini S, Balderamos M, Storey C, Patel AV, Kretzschmar D, Biehl ER, D’Mello SR. (2010) 1, 4- benzoxazine compounds as novel neuroprotective agents.  J. Neurosci. Res. 88: 1970-1984.

Ankanti H, Akubathini SK, D’Mello SR., Biehl ER (2010) Synthesis of 2-Benzylidene and 2-Hetarylmethyl Derivatives of 2H-1,4-Benzoxazin-3-(4H)-ones as Neuroprotective Agents” Synth. Communications 40: 2364–2376

Zhao K, Ippolito G, Wang L, Price V, Kim MH, Cornwell G, Fulenchek S, Breen GA, Goux WJ, D'Mello SR. (2010) Neuron-selective toxicity of tau peptide in a cell culture model of neurodegenerative tauopathy: essential role for aggregation in neurotoxicity. J Neurosci Res. 88:3399-3413.

Chen HL, D'Mello SR. (2010) Induction of neuronal cell death by paraneoplastic Ma1 antigen. J Neurosci Res. 88:3508-3519.

Dastidar SG, Landrieu PM, D'Mello SR. (2011) FoxG1 Promotes the Survival of Postmitotic Neurons. J Neurosci. 31:402-413.

Ma C, D'Mello SR. (2011) Neuroprotection by histone deacetylase-7 (HDAC7) occurs by inhibition of c-jun expression through a deacetylase-independent mechanism. J. Biol. Chem. 286:4819-4828.

Bardai FH, D’Mello SR. (2011) Selective toxicity by HDAC3 in neurons: Regulation by Akt and GSK3b.  J. Neurosci. 31:1746-51. (In the list of 50 most downloaded Journal of Neuroscience papers, March 2011)

Garcia-Oscos F, Salgado H, Hall S, Thomas F, Farmer GE, Bermeo J, Galindo LC, Ramirez RD, D'Mello S, Rose-John S, Atzori M. (2011) The stress-induced cytokine interleukin-6 decreases the inhibition/excitation ratio in the rat temporal cortex via trans-signaling. Biol Psychiatry. 71:574-582.

Ghosh Dastidar S, Bardai F, Ma C, Price V, Rawat V, Verma P, Narayanan V, D'Mello SR. (2012)  Isoform-specific toxicity of Mecp2 in postmitotic neurons: Suppression of neurotoxicity by FoxG1. J. Neurosci. 32:2846-2855.

Ghosh Dastidar S, Narayanan S, Stifani S, D’Mello  SR.  (2012) Transducin-like enhancer of Split-1 (TLE1) combines with Forkhead box protein G1 (FoxG1) to promote neuronal survival.  J Biol Chem. 287:14749-14759.

Bardai FH, Price V, Zaayman M, Wang L, D'Mello SR. (2012) Histone deacetylase (HDAC1) is a molecular switch between neuronal survival and death. J Biol Chem. 287:35444-35453.  (Paper of the week - Oct 12, 2012);  Best neuroscience paper in 2012)

Price V, Wang L, D’Mello SR (2013). Conditional deletion of HDAC4 in the CNS has no major effect on brain architecture or neuronal viability. J. Neurosci. Res. 91:407-15.

Bardai FH, Verma P, Smith C, Rawat V, Wang L, D’Mello SR. Disassociation of HDAC3 from normal huntingtin underlies mutant huntingtin neurotoxicity. J. Neurosci. (in press).


  • Updated: June 10, 2013