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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
United States
Zip Code
Spinelli, Edoardo G; Mandelli, Maria Luisa; Miller, Zachary A et al. (2017) Typical and atypical pathology in primary progressive aphasia variants. Ann Neurol 81:430-443
Berson, Amit; Sartoris, Ashley; Nativio, Raffaella et al. (2017) TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling. Curr Biol 27:3579-3590.e6
Nevler, Naomi; Ash, Sharon; Jester, Charles et al. (2017) Automatic measurement of prosody in behavioral variant FTD. Neurology 89:650-656
Cousins, Katheryn A Q; Ash, Sharon; Irwin, David J et al. (2017) Dissociable substrates underlie the production of abstract and concrete nouns. Brain Lang 165:45-54
Zylstra, Bradley; Netscher, George; Jacquemot, Julien et al. (2017) 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 :
Phillips, Jeffrey S; Da Re, Fulvio; Dratch, Laynie et al. (2017) Neocortical origin and progression of gray matter atrophy in nonamnestic Alzheimer's disease. Neurobiol Aging 63:75-87
Dong, Aoyan; Toledo, Jon B; Honnorat, Nicolas et al. (2017) Heterogeneity of neuroanatomical patterns in prodromal Alzheimer's disease: links to cognition, progression and biomarkers. Brain 140:735-747
Lee, Edward B; Porta, Sílvia; Michael Baer, G et al. (2017) Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration. Acta Neuropathol 134:65-78
Ballatore, Carlo; Brunden, Kurt R; Trojanowski, John Q et al. (2017) Non-Naturally Occurring Small Molecule Microtubule-Stabilizing Agents: A Potential Tactic for CNS-Directed Therapies. ACS Chem Neurosci 8:5-7
Kim, Benjamin J; Irwin, David J; Song, Delu et al. (2017) Optical coherence tomography identifies outer retina thinning in frontotemporal degeneration. Neurology 89:1604-1611

Showing the most recent 10 out of 549 publications