The project goal is to identify genes that modify tau pathogenicity. Two approaches will be used, both based on unbiased screens, and thus both can potentially reveal new features of taumediated toxicity. The first approach is to use human genetics to identify genes that contribute to risk for frontotemporal lobar dementia (FTLD). Previously we performed a genome-wide association study (GWAS) using progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) cases, both of which are FTLDs. Five genes were identified: MAPT, NELL2, the FAM76B/translokin/MTMR2 gene cluster, MOBP, and STX6. We will follow up on these loci, performing further human genetics studies and functional analysis. The second approach for identifying modifying loci is to use C. elegans as a tauopathy model. We will identify genes that suppress the toxic effects of tau in C. elegans and translate the finding into a mammalian model system.
The Specific Aims are: 1) Follow-up the PSP/CBD GWAS, by collecting additional PSP/CBD subjects, performing dense SNP mapping of the susceptibility genes, examine the expression of the PSP/CBD susceptibility genes with respect to genotype, and test these susceptibility genes in our C. elegans model. 2) Sequence genes involved in FTLD related neurodegenerative diseases. Subjects to be sequenced will primarily be FTLD cases. These experiments will identify rare variants that cause FTLD. 3) Identify new tau toxicity modifiers in our C. elegans model. 4) Generate a mouse knockout of an orthologue of a previously identified C. elegans suppressor gene (SUT2). These mice, null for the mammalian gene (mSUT2) will be crossed with a tau transgenic mouse PSI9 that develops a tauopathy-related phenotype. These experiments will determine if loss of mSUT2 can suppress tauopathy as SUT2 does in C. elegans. This project will identify genes that cause/modify tau toxicity, which is the key to undestanding FTLD. These findings will also be important to Alzheimer's disease, a disorder that also has prominent tau pathology.
This project will identify genes that contribute to the development of frontotemporal lobar dementia (FTLD). Understanding these genes will help determine what causes this disease to occur and what steps are important in the progression of this disease. These genes will also provide potential targets for the development of drugs to treat or prevent FTLD.
|Makani, Vishruti; Zhang, Bin; Han, Heeoon et al. (2016) Evaluation of the brain-penetrant microtubule-stabilizing agent, dictyostatin, in the PS19 tau transgenic mouse model of tauopathy. Acta Neuropathol Commun 4:106|
|Price, Amy Rose; Peelle, Jonathan E; Bonner, Michael F et al. (2016) Causal Evidence for a Mechanism of Semantic Integration in the Angular Gyrus as Revealed by High-Definition Transcranial Direct Current Stimulation. J Neurosci 36:3829-38|
|Santos-Santos, Miguel A; Mandelli, Maria Luisa; Binney, Richard J et al. (2016) Features of Patients With Nonfluent/Agrammatic Primary Progressive Aphasia With Underlying Progressive Supranuclear Palsy Pathology or Corticobasal Degeneration. JAMA Neurol 73:733-42|
|Ash, Sharon; Ternes, Kylie; Bisbing, Teagan et al. (2016) Dissociation of quantifiers and object nouns in speech in focal neurodegenerative disease. Neuropsychologia 89:141-52|
|Kovalevich, Jane; Cornec, Anne-Sophie; Yao, Yuemang et al. (2016) Characterization of Brain-Penetrant Pyrimidine-Containing Molecules with Differential Microtubule-Stabilizing Activities Developed as Potential Therapeutic Agents for Alzheimer's Disease and Related Tauopathies. J Pharmacol Exp Ther 357:432-50|
|Cousins, Katheryn A Q; Ash, Sharon; Irwin, David J et al. (2016) Dissociable substrates underlie the production of abstract and concrete nouns. Brain Lang 165:45-54|
|Shinagawa, Shunichiro; Catindig, Joseree Ann; Block, Nikolas R et al. (2016) When a Little Knowledge Can Be Dangerous: False-Positive Diagnosis of Behavioral Variant Frontotemporal Dementia among Community Clinicians. Dement Geriatr Cogn Disord 41:99-108|
|Vu, An T; Phillips, Jeffrey S; Kay, Kendrick et al. (2016) Using precise word timing information improves decoding accuracy in a multiband-accelerated multimodal reading experiment. Cogn Neuropsychol 33:265-75|
|McMillan, Corey T; Irwin, David J; Nasrallah, Ilya et al. (2016) Multimodal evaluation demonstrates in vivo (18)F-AV-1451 uptake in autopsy-confirmed corticobasal degeneration. Acta Neuropathol 132:935-937|
|Spiller, Krista J; Restrepo, Clark R; Khan, Tahiyana et al. (2016) Progression of motor neuron disease is accelerated and the ability to recover is compromised with advanced age in rNLS8 mice. Acta Neuropathol Commun 4:105|
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