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Email: zachdad@u.washington.edu

Researchers have found families with clusters of Alzheimer’s disease (AD), including early-onset cases with autosomal dominant inheritance. In 1984, the gene for the amyloid precursor protein (APP) was cloned. A fragment of the APP gene is the major component of the amyloid found in plaques in AD brain. Mutations in this gene causing early-onset autosomal dominant AD were identified in 1990. When Schellenberg's Laboratory evaluated the APP gene in the Seattle collection of AD families, no mutations were found, and it was immediately apparent that APP mutations are a rare cause of familial AD.

Frontotemporal Dementia with Parkinsonis—Chromosome 17 type (FTDP-17) is an autosomal dominant disorder that was mapped by linkage analysis to 17q21-22. Tau was known to be in the general region of this linkage. Initial DNA sequence analysis of tau by other groups failed to identify mutations. We sequenced the coding regions and 50-100 bp of flanking intronic sequence is samples from affected subjects in a Seattle family study group. The mutation M337V that co-segregated with the disease was not present in a large number of controls. This was the first tau mutation identified. To date, over 22 different FTDP-17 mutations have been described, including mis-sense mutations that alter the biochemical properties of tau.

Our primary goal is to identify chromosomal locations of genes that are AD susceptibility loci. Once these locations are identified, we will use positional cloning methods to identify these genes. Presently we are pursuing cloning of a late-onset AD (LOAD) gene on chromosome 19p. We are also using genetic linkage analysis to identify chromosomal regions containing genes for LOAD and genes that modify onset age in presenilin 2 (PS2) mutation families.

We are in the process of identifying the trans-acting proteins that interact with tau-regulatory elements. We are attempting to model FTDP-17 in mice and in C. elegans. In mice, we have inserted both normal and FTDP-17 mutant tau into transgenic animals. We will continue to generate different transgenic animals to reproduce an animal model of tau-related neurodegenerative disease.

Dr. Schellenberg is Research Professor, Medicine (Division of Gerontology and Geriatric Medicine), Neurology, and Pharmacology, and Associate Director for Research, Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center, Seattle. He served on the Neurosciences 3/BrainDisorders and Clinical Neurosciences-3 Study Section, 1996-2000, and currently participates on the National Advisory Council for Genome Research.

Selected Relevant Publications
Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Geschwind DH, Bird TD, McKeel D, Morris JC, Wilhelmsen KC, Schellenberg GD, Trojanowski JQ, Lee VM-Y. Mutation-specific functional impairments in distinct tau isoforms of hereditary frontotemporal dementia and Parkinsonism linked to chromosome 17: Genotype predicts phenotype. Science 282:1914-1917, 1998.

Clark LN, Poorkaj P, Wszolek Z, Geschwind DH, Nasreddine ZS, Miller B, Payami H, Awert F, Markopoulou K, D’Souza I, Lee VM-Y, Trojanowski J, Zhukareva V, Bird TD, Schellenberg GD, Wilhelmsen KC. Pathologic implications of mutations in the tau gene in Pallido-Ponto-Nigral degeneration and related chromosome 17-linked neurodegenerative disorders. Proc Natl Acad Sci USA 95:13103-13107, 1998.

D’Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM-Y, Bird TD, Schellenberg GD. Missense and silent tau gene mutations cause Fronto-temporal Dementia with Parkinsonism - Chromosome 17 Type by affecting multiple alternative RNA splicing regulatory elements. Proc Natl Acad Sci USA 96:5598-5603, 1999.

Brophy VH, Jarvik GP, Richter RJ, Rozek LS, Schellenberg GD, Furlong CE. Analysis of paraoxonase (PON1) L55M status requires both genotype and phenotype. Pharmacogenet 10:453-460, 2000.

Jarvik GP, Rozek LS, Brophy VH, Hatsukami TS, Richter RJ, Schellenberg GD, Furlong CE. Paraoxonase phenotype is a better predictor of vascular disease than PON1192 or PON155 genotype. Arterioscler Thromb Vasc Biol 20:2441-2447, 2000.

Daw EW, Payami H, Nemens EJ, Nochlin D, Bird TD, Schellenberg GD, Wijsman EM. The number of trait loci in late-onset Alzheimer disease. Am J Hum Genet 66:196-204, 2000.

Poorkaj P, Kas A, D’Souza I, Zhou Y, Pham O, Olson MV, Schellenberg GD. Comparison of the genomic sequences encoding the mouse and human microtubule associated protein tau. Mamm Genome 12:700-712, 2001.

Poorkaj P, Tsuang D, Wijsman EM, Nemens E, Garruto RM, Craig U, Anderson L-J, Bird TD, Plato CC, Weiderholt W, Galasko D, Schellenberg GD. Tau is a candidate gene for amyotropic lateral sclerosis-parkinsonism dementia complex of Guam. Arch Neurol 58:1871-1879, 2001.

Galasko D, Salmon DP, Craig U-K, Thal LJ, Schellenberg GD, Wiederholt W. Clinical features and changing patterns of neurodegenerative disorders on Guam, 1997-2000. Neurology 58:90-97, 2002.