Ataxia-telangiectasia (A-T) is a profoundly destructive childhood disorder resulting from mutation of a gene encoding a member of the PI3 kinase family. The gene, named ataxia- telangiectasia mutated (ATM) is a recognized component of the response mechanism to DNA double strand breaks. Yet, the consequences of ATM mutation include dramatic neurological deficiencies, and while some features of A-T can be explained by a faulty response to DNA damage, it is hard to fully account for the neurological aspects of the disease on this basis. The core hypothesis of this application is that there is a nervous system-specific form of ATM that is cytoplasmic. In this location, it serves as a serine-threonine kinase but equally as a chaperone protein that nucleates a complex of proteins that includes vesicle proteins such as synapsin-I and VAMP2. We propose that it is the failure of the functions associated with cytoplasmic ATM that leads to many of the neurological symptoms of A-T. We will explore this hypothesis in a two-part strategy.
Our first aim i s to expand our understanding of the role of ATM as a nucleocytoplasmic protein in neurons, and to uncover the unique functions that are enabled by its dual localization. We will explore how cytoplasmic ATM contributes to neuronal function on its own, and how it coordinates its action with its counterpart in the nucleus. Our outcome measures will include dendritic morphology, synaptic physiology, cell cycle regulation and cell survival. The second part of our strategy will be to develop strong pre-clinical platforms, both in vivo and in vitro, to test several agents currently under study in the clinic. We provide preliminary data showing that the well-described diversity of phenotype in human A-T is mimicked successfully in the mouse, provided that the correct set of alleles is chosen for analysis. We will use this newly expanded view of the mouse models to test the involvement of ATM in the neuronal response to stresses such as excitotoxicity, DNA damage and oxidative stress. Using the same outcome measures as above we will specifically test wild type and Atm- deficient cells for their response to stress and compare anti-oxidant and anti-inflammatory strategies for the potency as protective agents. Successful leads will be followed by in vivo trials comparing wild type with two different Atm mutations and their compound heterozygote. In a final series of pilot experiments we will explore whether ATM malfunction plays a role in other neurodegenerative disease. In the aggregate these studies offer a new look at the neurological deficits associated with A-T and, through the development of in vitro and in vivo model systems, brings fresh momentum to the discovery of treatments for this devastating condition.

Public Health Relevance

The dynamic behavior of the ATM protein in the neuronal cytoplasm and the discovery of its intimate association with proteins involved in synaptic vesicle behavior argue that there are facets of the neurobiology of ataxia-telangiectasia that remain to be discovered. The experiments proposed will bring new insights and offer fresh clues to the progress of ataxia-telangiectasia and other neurological diseases, of which Alzheimer's disease is only one example. The exploration of these phenomena will thus have significant value for our basic biological understanding of brain function as well as its malfunction in a number of different clinically relevant situations.

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
Gwinn, Katrina
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rutgers University
Anatomy/Cell Biology
Schools of Arts and Sciences
New Brunswick
United States
Zip Code
Yang, Yan; Hui, Chin Wai; Li, Jiali et al. (2014) The interaction of the atm genotype with inflammation and oxidative stress. PLoS One 9:e85863
Bhaskar, Kiran; Maphis, Nicole; Xu, Guixiang et al. (2014) Microglial derived tumor necrosis factor-* drives Alzheimer's disease-related neuronal cell cycle events. Neurobiol Dis 62:273-85
Herrup, Karl; Li, Jiali; Chen, Jianmin (2013) The role of ATM and DNA damage in neurons: upstream and downstream connections. DNA Repair (Amst) 12:600-4
Herrup, Karl (2013) Post-mitotic role of the cell cycle machinery. Curr Opin Cell Biol 25:711-6
Herrup, Karl (2013) ATM and the epigenetics of the neuronal genome. Mech Ageing Dev 134:434-9
Li, Jiali; Chen, Jianmin; Ricupero, Christopher L et al. (2012) Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia telangiectasia. Nat Med 18:783-90
Li, Jiali; Chen, Jianmin; Vinters, Harry V et al. (2011) Stable brain ATM message and residual kinase-active ATM protein in ataxia-telangiectasia. J Neurosci 31:7568-77