The prevalence of neurodegenerative disorders similar to Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS) is unusually high among Chamorros in the Mariana Islands. Despite similarities between these Chamorro diseases (known as Guam ALSIPDC) and AD, PD or ALS elsewhere, the predominant findings in Guam ALS/PDC brains are abundant neurofibrillary tangles (NE;Ts) like those in classic AD. For example, the major structural elements of NFTs AD and Guam ALS/PDC are paired helical filaments (PHFs), and previous studies showed that the PHFs in AD and Guam ALSIPDC are formed from abnormally phosphorylated tau proteins (PHFtau). Although, we showed that biopsy derived normal adult human tau is phosphorylated at nearly all of the sites previously identified in AD PHFtau, albeit to a lesser extent, biopsy derived normal human tau undergoes rapid and selective dephosphorylation at sites that are abnormally retained in PHFtau. We also provided data to suggest that differences in the phosphorylation state of normal human tau versus PHFtau may be due to impaired phosphatase activity in the AD brain. Indeed, protein phosphatase 2A (PP2A) was implicated in the failure of PHFtau to undergo efficient dephosphorylation. Since PP2A dephosphorylates tau, alterations in the accessory, catalytic and regulatory subunits of PP2A could play a central role in the generation of PHFtau. Although the degeneration of neurons in Guam ALSIPDC is associated almost exclusively with the accumulation of NFTs, and the levels of tan in the cerebrospinal fluid (CSF) of AD patients are elevated relative to controls, the pathogenesis and biological significance of accumulations of PHFtau in neurofibrillary lesions in AD and Guam ALS/PDC are poorly understood. Thus, Project 4 will test the hypothesis that PHFtau-rich neurofibrillary lesions play a role in the degeneration of neurons in Guam ALS/PDC. To accomplish this, we will assess the biological significance of elevated levels of CSF tan, examine the role of PP2A in the pathogenesis of PHFtau and tangle formation, and characterize the molecular profile of tangle bearing versus normal neurons in the brains of patients with and without Guam ALS/PDC. These studies will provide important insights into the pathogenesis of PHFtau in the hallmark lesions of Guam ALS/PDC, and clarify how these lesions lead to neuron loss in Guam ALS/PDC.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
3P01AG014382-03S1
Application #
6098725
Study Section
Project Start
1999-07-01
Project End
2000-02-29
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Dombroski, Beth A; Galasko, Douglas R; Mata, Ignacio F et al. (2013) C9orf72 hexanucleotide repeat expansion and Guam amyotrophic lateral sclerosis-Parkinsonism-dementia complex. JAMA Neurol 70:742-5
Brunden, Kurt R; Ballatore, Carlo; Lee, Virginia M-Y et al. (2012) Brain-penetrant microtubule-stabilizing compounds as potential therapeutic agents for tauopathies. Biochem Soc Trans 40:661-6
Lee, Virginia M-Y; Brunden, Kurt R; Hutton, Michael et al. (2011) Developing therapeutic approaches to tau, selected kinases, and related neuronal protein targets. Cold Spring Harb Perspect Med 1:a006437
Yu, Chang-En; Bird, Thomas D; Bekris, Lynn M et al. (2010) The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration. Arch Neurol 67:161-70
Brunden, Kurt R; Ballatore, Carlo; Crowe, Alex et al. (2010) Tau-directed drug discovery for Alzheimer's disease and related tauopathies: a focus on tau assembly inhibitors. Exp Neurol 223:304-10
Crowe, Alex; Huang, Wenwei; Ballatore, Carlo et al. (2009) Identification of aminothienopyridazine inhibitors of tau assembly by quantitative high-throughput screening. Biochemistry 48:7732-45
Brunden, Kurt R; Trojanowski, John Q; Lee, Virginia M-Y (2009) Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies. Nat Rev Drug Discov 8:783-93
Snyder, L R; Cruz-Aguado, R; Sadilek, M et al. (2009) Lack of cerebral bmaa in human cerebral cortex. Neurology 72:1360-1
Choi, Yoonha; Wijsman, Ellen M; Weir, Bruce S (2009) Case-control association testing in the presence of unknown relationships. Genet Epidemiol 33:668-78
Sieh, Weiva; Choi, Yoonha; Chapman, Nicola H et al. (2009) Identification of novel susceptibility loci for Guam neurodegenerative disease: challenges of genome scans in genetic isolates. Hum Mol Genet 18:3725-38

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