Different tau mutations cause FTD by different mechanisms; in some cases, the biochemical properties of tau are altered while in others, splicing of exon 10 (El0) is altered. Mutations affecting splicing act by altering at least 4 different regulatory mechanisms: 1) the strength of the 5' splice site of E10; 2) an exon splicing enhancer regulatory element in E10; 3) an exon splicing silencer in E10; and 4) an inhibitory sequence directly adjacent to the 3' end of E10. FTD mutations either increase or decrease E10 incorporation into tau mRNA. In some families that show linkage to chromosome 17, no mutations in the open reading frame of tau or in sequences directly flanking exons have been found. Also, for progressive supranuclear palsy (PSP), association studies demonstrate that tau genetic variability is a risk factor for PSP, yet no mutations/risk factors are present in the open reading frame of tau. Thus, additional regulatory mutations in intronic sequences not directly adjacent to exons remain to be found. The different mechanisms affected by the different mutations are responsible for the diverse phenotype observed in different FTD kindred. The following will be performed: 1) additional FTD families will be screened for tau mutations; 2) sporadic FTD subjects will be screened for mutations; 3) the functional consequences of each mutation on RNA splicing and tau protein function will be determined; 4) a P1 artificial chromosome (PAC) clone containing the complete tau gene will be characterized for use in generating transgenic animals; 5) tau mutations will be introduced into the PAC; 6) the normal and mutated PACs will be used to generate transgenic animals. This work will determine how tau mutations function in vivo and generate transgenic animals with tau pathology.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG017586-06
Application #
6851876
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (O4))
Project Start
2005-03-15
Project End
2010-02-28
Budget Start
2005-03-15
Budget End
2006-02-28
Support Year
6
Fiscal Year
2005
Total Cost
$242,710
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Lleó, Alberto; Irwin, David J; Illán-Gala, Ignacio et al. (2018) A 2-Step Cerebrospinal Algorithm for the Selection of Frontotemporal Lobar Degeneration Subtypes. JAMA Neurol 75:738-745
Grossman, Murray (2018) Linguistic Aspects of Primary Progressive Aphasia. Annu Rev Linguist 4:377-403
He, Zhuohao; Guo, Jing L; McBride, Jennifer D et al. (2018) Amyloid-? plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med 24:29-38
Healey, Meghan L; Grossman, Murray (2018) Cognitive and Affective Perspective-Taking: Evidence for Shared and Dissociable Anatomical Substrates. Front Neurol 9:491
Zylstra, Bradley; Netscher, George; Jacquemot, Julien et al. (2018) Extended, continuous measures of functional status in community dwelling persons with Alzheimer's and related dementia: Infrastructure, performance, tradeoffs, preliminary data, and promise. J Neurosci Methods 300:59-67
Karch, Celeste M; Wen, Natalie; Fan, Chun C et al. (2018) Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum. JAMA Neurol 75:860-875
Zhang, Ming; Ferrari, Raffaele; Tartaglia, Maria Carmela et al. (2018) A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers. Brain 141:2895-2907
Seo, Sang Won; Thibodeau, Marie-Pierre; Perry, David C et al. (2018) Early vs late age at onset frontotemporal dementia and frontotemporal lobar degeneration. Neurology 90:e1047-e1056
Chung, Chia-Yu; Berson, Amit; Kennerdell, Jason R et al. (2018) Aberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity. Nat Commun 9:4406
Kovacs, Gabor G; Kwong, Linda K; Grossman, Murray et al. (2018) Tauopathy with hippocampal 4-repeat tau immunoreactive spherical inclusions: a report of three cases. Brain Pathol 28:274-283

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