The overall goal of this project is to understand the mechanisms that govern death of neurons both in normal developmental and as a calamitous response to disease and injury. Understanding the former satisfies our curiosity and provides insight into how our nervous system is formed. Unraveling the latter may give us tools to treat neurodegenerative disorders, stroke and trauma. Our focus will be on the roles of transcription- dependent events and the pathways that regulate them in promoting neuron survival and death. Specifically, we will focus on two major pathways that mediate neuron death in a variety of circumstances relevant to both development and disease. These are the apoptotic """"""""cell cycle"""""""" and """"""""JNK"""""""" pathways. In each case, we will seek to extend (in both distal and proximal directions). our current knowledge about the component molecules that define and regulate these pathways. For the cell cycle pathway we will test the hypotheses that: a) The cell cycle regulatory protein Sei-1 plays a major role in initiating the pathway by interacting with and activating cyclin-dependent kinase 4 (Cdk4);b) Optimal promotion of neuron death occurs by a """"""""coincidence"""""""" mechanism in which transcription factors regulated by the cell cycle, JNK and additional pathways simultaneously converge on promoters of pro-apoptotic proteins such as Bim and Puma. In contrast, the choice of the death proteins that are transcriptionally regulated (e.g. Bim vs. Puma) depends on the apoptotic stimulus and is dictated by a combinatorial transcription factor mechanism;c) The apoptotic proteins DP5(Hrk) and EglN3(Sm- 20) are also subject to regulation by the cell cycle pathway via the coincidence mechanism and these converge with Bim to promote efficient neuron death;and d) Components of the apoptotic cell cycle pathway uncovered in our cell culture models will also be relevant to neuron death caused by injury and disease and specifically, in Alzheimer's Disease.(AD). For the JNK pathway we will assess the hypotheses that: a) In healthy neurons, the apoptotic JNK pathway is suppressed by the POSH-related molecule POSH2 and the E3 ligase Cbl;that these promote destabilization of the required POSH scaffold protein and that in response to apoptotic stimuli, POSH2 and Cbl are lost/inactivated, leading to POSH stabilization and pathway initiation;b) Activation of the apoptotic JNK pathway requires translocation of its kinase components to the perinuclear region in a complex containing the scaffolds POSH and the JNK-interacting protein (JIP). In healthy neurons, JIP is localized to neurites and POSH levels are very low. In response to apoptotic stimuli, POSH is stabilized, binds JIPs and the complex (along with active JNKs) is actively translocated to the perinuclear region where it promotes death;and c) Components of the apoptotic JNK pathway uncovered in our cell culture models will also be relevant to neuron death caused by injury and disease and specifically, in Alzheimer's Disease (AD). These studies are anticipated to significantly enhance our understanding of how neurons die during development and in disease and to uncover potential targets and treatments to alleviate the latter.

Public Health Relevance

This project seeks to uncover the specific biochemical pathways by which neurons die under circumstances relevant to both normal development and disease. The components of these pathways thus represent targets that can be used to block neuron death and ameliorate diseases such as neurodegenerative disorders, stroke and trauma.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Corriveau, Roderick A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Schools of Medicine
New York
United States
Zip Code
Liu, Jin; Amar, Fatou; Corona, Carlo et al. (2018) Brain-Derived Neurotrophic Factor Elevates Activating Transcription Factor 4 (ATF4) in Neurons and Promotes ATF4-Dependent Induction of Sesn2. Front Mol Neurosci 11:62
Park, Soyeon; Burke, Robert E; Kareva, Tatyana et al. (2018) Context-dependent expression of a conditionally-inducible form of active Akt. PLoS One 13:e0197899
Biswas, Subhas Chandra; Sanphui, Priyankar; Chatterjee, Nandini et al. (2017) Cdc25A phosphatase: a key cell cycle protein that regulates neuron death in disease and development. Cell Death Dis 8:e2692
Chatterjee, Nandini; Sanphui, Priyankar; Kemeny, Stav et al. (2016) Role and regulation of Cdc25A phosphatase in neuron death induced by NGF deprivation or ?-amyloid. Cell Death Discov 2:16083
Cates, Charles C; Arias, Angelo D; Nakayama Wong, Lynn S et al. (2016) Regression/eradication of gliomas in mice by a systemically-deliverable ATF5 dominant-negative peptide. Oncotarget 7:12718-30
Jean, Ying Y; Ribe, Elena M; Pero, Maria Elena et al. (2013) Caspase-2 is essential for c-Jun transcriptional activation and Bim induction in neuron death. Biochem J 455:15-25
Akpan, Nsikan; Troy, Carol M (2013) Caspase inhibitors: prospective therapies for stroke. Neuroscientist 19:129-36
Zareen, N; Biswas, S C; Greene, L A (2013) A feed-forward loop involving Trib3, Akt and FoxO mediates death of NGF-deprived neurons. Cell Death Differ 20:1719-30
Grau, Cristina Malagelada; Greene, Lloyd A (2012) Use of PC12 cells and rat superior cervical ganglion sympathetic neurons as models for neuroprotective assays relevant to Parkinson's disease. Methods Mol Biol 846:201-11
Chalazonitis, Alcmène; Gershon, Michael D; Greene, Lloyd A (2012) Cell death and the developing enteric nervous system. Neurochem Int 61:839-47

Showing the most recent 10 out of 29 publications