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

Petok, Jessica R; Myers, Catherine E; Pa, Judy et al. (2018) Impairment of memory generalization in preclinical autosomal dominant Alzheimer's disease mutation carriers. Neurobiol Aging 65:149-157
Brenowitz, Willa D; Han, Fang; Kukull, Walter A et al. (2018) Treated hypothyroidism is associated with cerebrovascular disease but not Alzheimer's disease pathology in older adults. Neurobiol Aging 62:64-71
Davis, Jeremy J (2018) Performance validity in older adults: Observed versus predicted false positive rates in relation to number of tests administered. J Clin Exp Neuropsychol 40:1013-1021
Cruchaga, Carlos; Del-Aguila, Jorge L; Saef, Benjamin et al. (2018) Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms. Alzheimers Dement 14:205-214
Lin, Ming; Gong, Pinghua; Yang, Tao et al. (2018) Big Data Analytical Approaches to the NACC Dataset: Aiding Preclinical Trial Enrichment. Alzheimer Dis Assoc Disord 32:18-27
Gallagher, Damien; Kiss, Alex; Lanctot, Krista L et al. (2018) Toward Prevention of Mild Cognitive Impairment in Older Adults With Depression: An Observational Study of Potentially Modifiable Risk Factors. J Clin Psychiatry 80:
Kirson, Noam Y; Scott Andrews, J; Desai, Urvi et al. (2018) Patient Characteristics and Outcomes Associated with Receiving an Earlier Versus Later Diagnosis of Probable Alzheimer's Disease. J Alzheimers Dis 61:295-307
Weissberger, Gali H; Nation, Daniel A; Nguyen, Caroline P et al. (2018) Meta-analysis of cognitive ability differences by apolipoprotein e genotype in young humans. Neurosci Biobehav Rev 94:49-58
Wang, Junyan; Aydogan, Dogu Baran; Varma, Rohit et al. (2018) Modeling topographic regularity in structural brain connectivity with application to tractogram filtering. Neuroimage 183:87-98
Barnes, Josephine; Bartlett, Jonathan W; Wolk, David A et al. (2018) Disease Course Varies According to Age and Symptom Length in Alzheimer's Disease. J Alzheimers Dis 64:631-642

Showing the most recent 10 out of 590 publications