Neurons in the nervous system undergo retrograde degeneration in neurodegenerative diseases and after acute neurological insults. This grant was awarded previously to characterize an animal model of retrograde degeneration of neurons in the dorsal lateral geniculate nucleus (dLGN) induced by target ablation, and to identify molecular mediators of this cell death. We found that this retrograde neurodegeneration is apoptosis, unequivocally defined by its structure, mediation by Bax (a multidomain Bcl-2 family death effector) and p53, and caspase-3 signaling. This cell death emerges with accumulation of perikaryal mitochondria, oxidative damage to DNA, and subcellular translocations of death effectors, and is modulated by neuronal nitric oxide synthase (nNOS). Previous and new experiments, using in situ cell imaging, show that preapoptotic, target-deprived dLGN neurons accumulate mitochondria prior to cell body shrinkage. We hypothesize that these mitochondria are derived from the axon/synaptic terminals. In this grant renewal we will use our model of apoptosis in mouse brain, in which dLGN neurons undergo apoptosis over 7 days after occipital cortex ablation, to study mitochondrial mechanisms of apoptosis in neurons in vivo.
In Aim 1 we will identify sources of the accumulating mitochondria and will test the hypothesis that mitochondria return via dynein motors to the dLGN neuron cell body from the remote site of injury in an altered state defined by their capacity for generating reactive oxygen species (ROS) and content of BH3-only death proteins (Bad, Puma, and Noxa). New experiments also suggest that preapoptotic dLGN neurons accumulate intracellular Ca2+.
In Aim 2 we will identify possible mechanisms of intracellular Ca2+ accumulation and the preapoptotic roles of mitochondrial Ca uptake and calcineurin-mediated Bad dephosphorylation and mitochondrial translocation.
In Aim 3 we will examine the hypothesis that nNOS activation in target-deprived dLGN neurons leads to peroxynitrite production, intracellular Zn2+ accumulation, and mitochondrial dysfunction. This work can define a new mitochondrial mechanism for target deprivation-induced neurodegeneration and can improve the understanding of the cellular and molecular mechanisms of neuronal apoptosis in vivo

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG016282-09
Application #
7572839
Study Section
Special Emphasis Panel (ZRG1-NDBG (02))
Program Officer
Wise, Bradley C
Project Start
2000-03-01
Project End
2011-02-28
Budget Start
2009-04-01
Budget End
2011-02-28
Support Year
9
Fiscal Year
2009
Total Cost
$312,402
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Martin, Lee J; Wong, Margaret (2017) Enforced DNA repair enzymes rescue neurons from apoptosis induced by target deprivation and axotomy in mouse models of neurodegeneration. Mech Ageing Dev 161:149-162
Martin, Lee J; Semenkow, Samantha; Hanaford, Allison et al. (2014) Mitochondrial permeability transition pore regulates Parkinson's disease development in mutant ?-synuclein transgenic mice. Neurobiol Aging 35:1132-52
Martin, Lee J (2012) Biology of mitochondria in neurodegenerative diseases. Prog Mol Biol Transl Sci 107:355-415
Martin, Lee J; Chang, Qing (2012) Inhibitory synaptic regulation of motoneurons: a new target of disease mechanisms in amyotrophic lateral sclerosis. Mol Neurobiol 45:30-42
Gertz, Barry; Wong, Margaret; Martin, Lee J (2012) Nuclear localization of human SOD1 and mutant SOD1-specific disruption of survival motor neuron protein complex in transgenic amyotrophic lateral sclerosis mice. J Neuropathol Exp Neurol 71:162-77
Chavez-Valdez, R; Martin, L J; Flock, D L et al. (2012) Necrostatin-1 attenuates mitochondrial dysfunction in neurons and astrocytes following neonatal hypoxia-ischemia. Neuroscience 219:192-203
Martin, Lee J (2011) An approach to experimental synaptic pathology using green fluorescent protein-transgenic mice and gene knockout mice to show mitochondrial permeability transition pore-driven excitotoxicity in interneurons and motoneurons. Toxicol Pathol 39:220-33
Martin, Lee J (2011) Mitochondrial pathobiology in ALS. J Bioenerg Biomembr 43:569-79
Martin, Lee J; Adams, Neal A; Pan, Yan et al. (2011) The mitochondrial permeability transition pore regulates nitric oxide-mediated apoptosis of neurons induced by target deprivation. J Neurosci 31:359-70
Northington, Frances J; Chavez-Valdez, Raul; Martin, Lee J (2011) Neuronal cell death in neonatal hypoxia-ischemia. Ann Neurol 69:743-58

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