Molecular mechanisms regulating neurodegeneration & brain development
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. Our research has been funded by grants from the National Institutes of Health (NIH), Department of Defense, the National Science Foundation and private foundations. Our ongoing research on neurodegeneration and neurodevelopmental disorders is described below.
Neurodegenerative disorders
Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease (PD), and Huntington's disease (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), they do not slow down the relentless loss of neurons and therefore the disease progresses. Our lab is interested in identifying molecules that regulate the survival or death of neurons and whose altered function contributes to neurodegenerative disorders. Once identified, 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 deacetylation of non-histone proteins residing in the nucleus, cytoplasm or mitochondria. In studies supported by the NIH, we discovered that activation of one of the members of this family of proteins, HDAC3, plays a central role in promoting neurodegeneration. We are studying the mechanism by which HDAC3 promotes neurodegeneration.
The lab is also interested in FoxG1, a protein belonging to the Forkhead family of transcription factors 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 generated 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. Another Forkhead protein of interest to the lab is FoxP1. FoxP1 is expressed selectively in the striatum and cortex, two regions of the brain that are selectively degenerate in HD. In studies funded by the NIH we found that FoxP1 expression is reduced in the striatum of HD patients and in HD mouse models. This reduction likely contributes the the loss of neurons in HD. In humans, FoxP1 mutations cause mental retardation and other cognitive deficits.
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.
Neurodevelopmental disorders
We have recently become interested in MeCP2, a gene that can repress gene transcription globally as well as locally. Loss-of-function mutations in the MeCP2 gene cause Rett syndrome, a neurodevelopmental disorder characterized 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. On the other hand, elevated activity of MeCP2 as a result of gene duplication or triplication causes another neurological 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 with MeCP2 duplication syndrome, these mice display neurological deficits and die early in adulthood. The mice display neuronal loss in certain brain regions coincident with the neurological symptoms and 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 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, characterized by spasticity, mental retardation, and seizures. These symptoms are also observed in many patients with MeCP2 duplication syndrome. We are exploring whether MeCP2 duplication syndrome and Alexander disease share mechanistic commonalities.
While abnormal function of HDAC3 contributes to neurodegeneration, recent research in the lab on brain-specific conditional knockout mice has revealed that HDAC3 plays an essential role in brain development. Neuronal migration and formation of proper lamination in the cortex is disrupted in mice lacking HDAC3 in the brain. Exactly how HDAC3 regulates proper brain development is being studied.
Supernumerary neurons in the hippocampus Disrupted lamination in the cortex
of MeCP2 transgenic mice of HDAC3 conditional knockout mice
Selected publications
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 GSK3. 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 2012), Best neuroscience paper (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. (2013) Disassociation of HDAC3 from normal huntingtin underlies mutant huntingtin neurotoxicity. J. Neurosci. 33:11833-11838.
Rangaswamy S, D’Mello SR, Narayanan V (2013) Epigenetics, Autism Spectrum, and Neurodevelopmental Disorders. Neurotherapeutics 10:742-756.
Verma P, Pfister, JA, Mallick S, D’Mello SR (2014) HSF1 protects neurons through a novel trimerization and HSP independent mechanism. J Neurosci. 34:1599-1612.
Mallick S. and D'Mello SR. (2014) JAZ (Znf346), a SIRT1-interacting protein protects neurons by stimulating p21 (WAF/CIP1) expression. J. Biol. Chem. 289:35409-35420.
Norwood J, Franklin JM, Sharma D, D'Mello SR. (2014) Histone deacetylase-3 is necessary for proper brain development. J. Biol. Chem.289: 34569-34582.
Garcia-Oscos F, Peña D, Housini M, Cheng D, Lopez D, Borland MS, Salgado-Delgado R, Salgado H, D'Mello S, Kilgard MP, Rose-John S, Atzori M. (2015) Vagal nerve stimulation blocks interleukin 6-dependent synaptic hyperexcitability induced by lipopolysaccharide-induced acute stress in the rodent prefrontal cortex. Brain Behav Immun. 43: 149-158.
Sharma D, Kim MS, D'Mello SR (2015). Transcriptome profiling of expression changes during neuronal death by RNA-Seq. Exp. Biol. Med.. 240:242-51.
Selected as the feature article for the February 2015 issue. Was also featured in a press release.
Rawat V, Goux W, Piechaczyk M and D'Mello (2016) C-Fos protects neurons through a non-canonical mechanism involving HDAC3 interaction: Identification of a 21 amino acid fragment with neuroprotective activity. Mol. Neurobiology 53:1165-1180.
Pfister J and D'Mello SR. (2015) Insights into the regulation of neuronal viability by Nucleophosmin/B23. Experimental Biology and Medicine 240:774-786.
Smith C and D’Mello SR (2016) Cell and context-dependent effects of the heat shock protein DNAJB6 on neuronal survival. Mol. Neurobiol. 53: 5628-5639
Pfister JA and D’Mello SR (2016) Regulation of neuronal survival by nucleophosmin 1 (NPM1) is dependent on its expression level, subcellular localization and oligomerization status. J. Biol. Chem.291:20787-20797.
Louis Sam Titus ASC, Yusuff T, Cassar M, Thomas E, Kretzschmar D, D'Mello SR (2017) Reduced Expression of Foxp1 as a Contributing Factor in Huntington's Disease. J. Neurosci.37:6575-6587.
Thomas EA and D’Mello SR (2018). Complex neuroprotective and neurotoxic effects of histone deacetylases. J. Neurochem.145:96-110.
Qu, Z and D’Mello SR. (2018) Proteomic analysis identifies NPTX1 and HIP1R as potential targets of HDAC3-mediated neurodegeneration. Exp. Biol. Med. 243:627-638
Montgomery KR, ASC Louis Sam Titus, Wang L, D’Mello SR (2018) Elevated MeCP2 in Mice Causes Neurodegeneration Involving Tau Dysregulation and Excitotoxicity: Implications for the Understanding and Treatment of MeCP2 Triplication Syndrome. Molecular Neurobiology 55:9057-9074.
Qu Z, Xuan Z, D’Mello SR. Neuroprotection by Heat Shock Factor-1 (HSF1) and Trimerization-Deficient Mutant Identifies Novel Alterations in Gene Expression (2018). Sci Reports 8(1):17255.
Pfister JA, Ma Chi, D’Mello SR (2019) Catalytic-independent neuroprotection by SIRT1 is mediated through interaction with HDAC1. PLosOne 14(4):e0215208
Louis Sam Titus ACS, Sharma D, D’Mello SR. (2020) The BDNF and Npas4 genes are targets of HDAC3-mediated transcriptional repression. BMC Neuroscience 28;20(1):65.
D’Mello SR. (2020) Regulation of CNS Development by Class I HDACs. Developmental Neuroscience. 41:149-165.
D’Mello SR.(2020) Histone deacetylase-3: Friend and foe of the brain. Exp Biol Med 245:1130-1141.
D’Mello SR and Kindy M. (2020) Overdosing on iron: Elevated iron and degenerative brain disorders. Exp Biol Med 245:1444-1473
D’Mello SR (2021) When Good Kinases go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s disease. International Journal of Medical Sciences 22(11):5911. doi: 10.3390/ijms22115911).
D’Mello SR. (2021) MECP2 and the Biology of MeCP2 Duplication Syndrome. J. Neurochem. doi: 10.1111/jnc.15331. (Online ahead of print).
Teaching interests
Will be teaching Neuroscience-I (3 credits) and Molecular basis of brain development (3 credits) and degeneration starting Spring 2022 and Neuroscience-II in starting Fall 2022.
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