Abstract

Amyloid deposits are commonly found in neurodegenerative diseases. Alzheimer disease (AD) is characterized by several kinds of deposits: extracellular beta-amyloid containing plaques and intraneuronal tau-containing tangles and, quite often, alpha-synuclein-containing Lewy bodies. This proposal aims to determine the structure of amyloid fibrils formed by, alpha-synuclein through biochemical and biophysical methods. In particular, we will exploit recent advances in site-directed spin labeling and EPR spectroscopy to determine alpha-synuclein fibril structure. We will also use nitroxide-scanning experiments to determine the local secondary structure. This information in combination with mapping of inter- and intra-molecular distances should allow us to build 3-dimensional models of alpha-synuclein fibrils. Similar strategies will be used to determine the molecular mechanism of alpha-synuclein membrane interaction. Membrane interactions are implicated in the physiologic function of alpha-synuclein in presynaptic terminals of neurons, whereas mutations linked to neurodegeneration are known to modulate the membrane interactions of alpha-synuclein and to enhance the formation of amyloid fibrils.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005142-22
Application #
7063359
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
22
Fiscal Year
2005
Total Cost
$206,412
Indirect Cost

  Institution

Name
University of Southern California
Department
Type
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089

  Publications

Ting, Simon Kang Seng; Foo, Heidi; Chia, Pei Shi et al. (2018) Dyslexic Characteristics of Chinese-Speaking Semantic Variant of Primary Progressive Aphasia. J Neuropsychiatry Clin Neurosci 30:31-37
Gallagher, Damien; Kiss, Alex; Lanctot, Krista et al. (2018) Depression and Risk of Alzheimer Dementia: A Longitudinal Analysis to Determine Predictors of Increased Risk among Older Adults with Depression. Am J Geriatr Psychiatry 26:819-827
Haaksma, Miriam L; Calderón-Larrañaga, Amaia; Olde Rikkert, Marcel G M et al. (2018) Cognitive and functional progression in Alzheimer disease: A prediction model of latent classes. Int J Geriatr Psychiatry 33:1057-1064
Corlier, Fabian; Hafzalla, George; Faskowitz, Joshua et al. (2018) Systemic inflammation as a predictor of brain aging: Contributions of physical activity, metabolic risk, and genetic risk. Neuroimage 172:118-129
Nation, Daniel A; Tan, Alick; Dutt, Shubir et al. (2018) Circulating Progenitor Cells Correlate with Memory, Posterior Cortical Thickness, and Hippocampal Perfusion. J Alzheimers Dis 61:91-101
Ramsey, Christine M; Gnjidic, Danijela; Agogo, George O et al. (2018) Longitudinal patterns of potentially inappropriate medication use following incident dementia diagnosis. Alzheimers Dement (N Y) 4:1-10
Sweeney, Melanie D; Kisler, Kassandra; Montagne, Axel et al. (2018) The role of brain vasculature in neurodegenerative disorders. Nat Neurosci 21:1318-1331
Nation, Daniel A (2018) Blood Pressure and Cerebral Blood Flow in Alzheimer Disease. Hypertension 72:68-69
Hadjichrysanthou, Christoforos; McRae-McKee, Kevin; Evans, Stephanie et al. (2018) Potential Factors Associated with Cognitive Improvement of Individuals Diagnosed with Mild Cognitive Impairment or Dementia in Longitudinal Studies. J Alzheimers Dis 66:587-600
Hanfelt, John J; Peng, Limin; Goldstein, Felicia C et al. (2018) Latent classes of mild cognitive impairment are associated with clinical outcomes and neuropathology: Analysis of data from the National Alzheimer's Coordinating Center. Neurobiol Dis 117:62-71

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