Abnormally aggregates of the protein tau in the form of neurofibrillary tangles (NFT's) and glial tangles are found in a number of neurodegenerative diseases including Alzheimer's disease (AD) and frontotemporal dementia with parkinsonism - chromosome 17 type (FTDP-17). For most of these diseases, the role tau plays in disease initiation and progression is not understood. However, for the autosomal-dominant disorder FTDP-17, mutations in MAPT, the gene that encodes tau protein, cause the disease. The clinical and neuropathologic phenotype produced by different MAPT mutations is highly variable. For some mutations, the initial clinical feature is limited to executive function deterioration. For others, severe behavioral disturbances such as disinhibition or psychosis are the initial symptoms. Different neuropathologic phenotypes are observed. For some mutations, aggregated tau is only seen in neurons as NFT's. For others, both neuronal and glial aggregates are found (glial fibdllary tangles, GFT's). The regional distribution of pathology is also varied. In some cases, pathology is seen broadly distributed in the frontotemporal lobes while in other cases, only brain stem regions are involved as seen in progressive supra nuclear palsy (PSP). Two types of FTDP-17 mutations are known. One type is missense mutations that act at the protein level. The second type of mutations, which is the focus of this application, alter the regulation of the alternative splicing of tau exon 10 (El0). Also, susceptibility to PSP is caused by an unidentified allele(s) at a MAPT polymorphic site(s) that influences MAPTsplicing. For FTDP-17 mutations, phenotypic variability is potentially dependent on differential expression patterns of trans-acting splicing regulatory factors in different subpopulations of neurons and glial cells. Differential phosphorylation of trans-acting factors in different cell types may also be involved in phenotypic vadabUity. In this proposal, we will identify the cis-acting sequence elements in tau that affect the regulation of alternative splicing. We will also identify the trans-factors that interact with the cis-acting elements. Identification of c/s-elements may lead to therapeutic approaches based on evolving strategies for manipulating RNA in vivo. Likewise, identification of trans-factors may lead to protein targets such as kinases that are also therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG011762-18
Application #
8312586
Study Section
Special Emphasis Panel (NSS)
Program Officer
Miller, Marilyn
Project Start
1994-06-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
18
Fiscal Year
2012
Total Cost
$280,909
Indirect Cost
$105,341
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ryman, Davis C; Acosta-Baena, Natalia; Aisen, Paul S et al. (2014) Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 83:253-60
Stutzbach, Lauren D; Xie, Sharon X; Naj, Adam C et al. (2013) The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer's disease. Acta Neuropathol Commun 1:31
Höglinger, Günter U; Melhem, Nadine M; Dickson, Dennis W et al. (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43:699-705
Melrose, H L; Dachsel, J C; Behrouz, B et al. (2010) Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. Neurobiol Dis 40:503-17
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
McMillan, Pamela; Korvatska, Elena; Poorkaj, Parvoneh et al. (2008) Tau isoform regulation is region- and cell-specific in mouse brain. J Comp Neurol 511:788-803
Wijsman, Ellen M; Sung, Yun Ju; Buil, Alfonso et al. (2007) Summary of Genetic Analysis Workshop 15: Group 9 linkage analysis of the CEPH expression data. Genet Epidemiol 31 Suppl 1:S75-85
Sieh, Weiva; Yu, Chang-En; Bird, Thomas D et al. (2007) Accounting for linkage disequilibrium among markers in linkage analysis: impact of haplotype frequency estimation and molecular haplotypes for a gene in a candidate region for Alzheimer's disease. Hum Hered 63:26-34
D'Souza, Ian; Schellenberg, Gerard D (2006) Arginine/serine-rich protein interaction domain-dependent modulation of a tau exon 10 splicing enhancer: altered interactions and mechanisms for functionally antagonistic FTDP-17 mutations Delta280K AND N279K. J Biol Chem 281:2460-9

Showing the most recent 10 out of 16 publications