In neurodegenerative disorders such as Alzheimers, Parkinsons and Huntingtons diseases, neurons may die by a form of programmed cell death called apoptosis. A major effort in the Cellular and Molecular Neurosciences section of the Laboratory of Neurosciences is aimed at establishing what triggers apoptosis in neurodegenerative disorders and how neuronal degeneration might be prevented by targeting specific molecular events in the process of apoptosis. We have found that a protein called p53 is involved in the death of neurons in experimental models of Alzheimers, Parkinsons and Huntingtons diseases. Novel specific inhibitors of p53 were developed and several lead agents were shown to be effective in animal models of stroke and Parkinsons disease. In other studies we established important roles for potassium ion fluxes in the pathogenesis of neuronal degeneration in models of stroke. A drug called diazoxide that opens mitochondrial potassium channels was neuronprotective in models of stroke. In studies of the mechanism by which neurons die in Alzheimers disease we have found that damage to DNA causes the neurons to undergo an abortive attempt to re-enter the cell cycle resulting in activation of the ATM kinase and p53 which trigger apoptosis. Our studies of telomere function in neurons have revealed roles for several telomere-associated proteins in preventing apoptosis. Damage to mitochondrial DNA may also trigger apoptosis, but a DNA repair protein called OGG1 can protect neurons from dying in models of neurodegenerative disorders. In addition, we have identified a mitochondrial uncoupling protein (UCP4) that can protect neurons in models relevant to stroke and Alzheimers disease by a mechanism involving suppression of oxidative stress and stabilization of cellular calcium homeostasis. We have also established roles for brain-derived neurotrophic factor (BDNF) in preventing the apoptosis of neurons produced from stem cells in the hippocampus, a finding that suggests the possibility of increasing the capacity of the brain to replace lost and damaged neurons. In other studies we have found that newly generated neurons are highly sensitive to DNA damage-induced apoptosis because they have low levels of telomerase and the telomere-associated protein TRF2. More recently, we established roles for Notch signaling and a novel protein called Pancortin-2 in neuronal death in stroke. Preclinical studies have shown that intravenous immunoglobulin and gamma-secretase inhibotors are effective in stroke models.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000313-07
Application #
7591984
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2007
Total Cost
$938,026
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Gleichmann, Marc; Zhang, Yongqing; Wood 3rd, William H et al. (2012) Molecular changes in brain aging and Alzheimer's disease are mirrored in experimentally silenced cortical neuron networks. Neurobiol Aging 33:205.e1-18
Gong, Eun Ji; Park, Hee Ra; Kim, Mi Eun et al. (2011) Morin attenuates tau hyperphosphorylation by inhibiting GSK3?. Neurobiol Dis 44:223-30
Stutzmann, Grace E; Mattson, Mark P (2011) Endoplasmic reticulum Ca(2+) handling in excitable cells in health and disease. Pharmacol Rev 63:700-27
Yoon, Jeong Seon; Lee, Jong-Hwan; Son, Tae Gen et al. (2011) Pregabalin suppresses calcium-mediated proteolysis and improves stroke outcome. Neurobiol Dis 41:624-9
Romberg, Carola; Mattson, Mark P; Mughal, Mohamed R et al. (2011) Impaired attention in the 3xTgAD mouse model of Alzheimer's disease: rescue by donepezil (Aricept). J Neurosci 31:3500-7
Bruestle, Daniel A; Cutler, Roy G; Telljohann, Richard S et al. (2009) Decline in daily running distance presages disease onset in a mouse model of ALS. Neuromolecular Med 11:58-62
Mattson, Mark P; Ashery, Uri (2009) No more brain tangles with DeltaNp73. Trends Biochem Sci 34:6-8
Mattson, Mark P; Wan, Ruiqian (2008) Neurotrophic factors in autonomic nervous system plasticity and dysfunction. Neuromolecular Med 10:157-68
Liu, Manchang; Liang, Yideng; Chigurupati, Srinivasulu et al. (2008) Acute kidney injury leads to inflammation and functional changes in the brain. J Am Soc Nephrol 19:1360-70
Wilson 3rd, David M; Mattson, Mark P (2007) Neurodegeneration: nicked to death. Curr Biol 17:R55-8

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