Regulated neuronal death by apoptosis is a key part of normal brain development. Unfortunately, neuronal apoptosis is also triggered after brain injury or in neurodegenerative disease, where it contributes to the loss of neurons and the resulting neurological deficits. Thus, the neuronal apoptosis pathway is of physiological and pathological importance. Recent studies have reported an age-dependent decline in the incidence of apoptosis in the brain. However, the mechanisms of these changes are not well studied, and its implications on how apoptosis is activated in neuropathological situations in young versus adult neurons are unclear. Our long-term objectives are to understand the molecular mechanisms by which apoptosis is regulated in neurons, with a specific interest in identifying age-related changes in this pathway. Our focus is on the mechanism of activation of caspase proteases, which are the central executioners of apoptosis. A major pathway of caspase activation involves the mitochondrial release of cytochrome c and subsequent formation of the Apaf-1-dependent apoptosome complex. Our results have identified distinct age-dependent changes in which the cytochrome c-dependent caspase activation pathway becomes increasingly inhibited in neurons. For example, we find that caspase activation in neurons during early development is strictly and selectively regulated by XIAP.
In Specific Aim 1, we will examine how XIAP's strict control of caspases is overcome to permit caspase activation in physiological (NGF deprivation) and pathological (ER stress) models of sympathetic neuronal apoptosis. We will also examine whether XIAP-deficient neurons are more vulnerable to neuronal injury in vitro and in vivo. We will examine this in neurodegeneration models of mutant superoxide dismutase 1 (SOD1) overexpression and neonatal hypoxia-ischemia. At later stages of development, we find that neurons engage additional mechanisms to inhibit apoptosis.
In Specific Aim 2, we will focus on identifying the posttranslational mechanism that inactivates Apaf-1 in neurons during the late period of cerebellar development. Finally, as neurons mature, they appear to turn off the expression of Apaf-1 and caspase-3 altogether.
In Specific Aim 3 we will test whether the cell cycle- related protein E2F1, which is known to be expressed in dying neurons, is important for restoring Apaf-1 expression and permitting cytochrome c-mediated apoptosis in mature neurons. Understanding the mechanism by which apoptosis is regulated in neurons is clinically important for identifying appropriate drug targets that would effectively prevent neuronal death after injury or disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042197-10
Application #
8134319
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Gubitz, Amelie
Project Start
2001-09-01
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
10
Fiscal Year
2011
Total Cost
$310,749
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Annis, Ryan P; Swahari, Vijay; Nakamura, Ayumi et al. (2016) Mature neurons dynamically restrict apoptosis via redundant premitochondrial brakes. FEBS J 283:4569-4582
Nakamura, Ayumi; Swahari, Vijay; Plestant, Charlotte et al. (2016) Bcl-xL Is Essential for the Survival and Function of Differentiated Neurons in the Cortex That Control Complex Behaviors. J Neurosci 36:5448-61
Swahari, Vijay; Nakamura, Ayumi; Baran-Gale, Jeanette et al. (2016) Essential Function of Dicer in Resolving DNA Damage in the Rapidly Dividing Cells of the Developing and Malignant Cerebellum. Cell Rep 14:216-24
Knight, E R W; Patel, E Y; Flowers, C A et al. (2015) ASC deficiency suppresses proliferation and prevents medulloblastoma incidence. Oncogene 34:394-402
Cliffe, Anna R; Arbuckle, Jesse H; Vogel, Jodi L et al. (2015) Neuronal Stress Pathway Mediating a Histone Methyl/Phospho Switch Is Required for Herpes Simplex Virus Reactivation. Cell Host Microbe 18:649-58
Crowther, Andrew J; Gama, Vivian; Bevilacqua, Ariana et al. (2013) Tonic activation of Bax primes neural progenitors for rapid apoptosis through a mechanism preserved in medulloblastoma. J Neurosci 33:18098-108
Gama, Vivian; Deshmukh, Mohanish (2013) Adenosine: essential for life but licensed to kill. Mol Cell 50:307-8
Kole, A J; Annis, R P; Deshmukh, M (2013) Mature neurons: equipped for survival. Cell Death Dis 4:e689
Cusack, Corey L; Swahari, Vijay; Hampton Henley, W et al. (2013) Distinct pathways mediate axon degeneration during apoptosis and axon-specific pruning. Nat Commun 4:1876
Uribe, Valeria; Wong, Bibiana K Y; Graham, Rona K et al. (2012) Rescue from excitotoxicity and axonal degeneration accompanied by age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice. Hum Mol Genet 21:1954-67

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