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
Russ, Jenny; Liu, Elaine Y; Wu, Kathryn et al. (2015) Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier. Acta Neuropathol 129:39-52
Massimo, Lauren; Evans, Lois K (2014) Differentiating subtypes of apathy to improve person-centered care in frontotemporal degeneration. J Gerontol Nurs 40:58-65
Ferrari, Raffaele; Hernandez, Dena G; Nalls, Michael A et al. (2014) Frontotemporal dementia and its subtypes: a genome-wide association study. Lancet Neurol 13:686-99
Olm, Christopher A; McMillan, Corey T; Spotorno, Nicola et al. (2014) The relative contributions of frontal and parietal cortex for generalized quantifier comprehension. Front Hum Neurosci 8:610
Serrano, Geidy E; Sabbagh, Marwan N; Sue, Lucia I et al. (2014) Positive florbetapir PET amyloid imaging in a subject with frequent cortical neuritic plaques and frontotemporal lobar degeneration with TDP43-positive inclusions. J Alzheimers Dis 42:813-21
Irwin, David J; McMillan, Corey T; Suh, EunRan et al. (2014) Myelin oligodendrocyte basic protein and prognosis in behavioral-variant frontotemporal dementia. Neurology 83:502-9
Alfieri, Julio A; Pino, Natalia S; Igaz, Lionel M (2014) Reversible behavioral phenotypes in a conditional mouse model of TDP-43 proteinopathies. J Neurosci 34:15244-59
Walker, Adam K; Daniels, Christine M LaPash; Goldman, James E et al. (2014) Astrocytic TDP-43 pathology in Alexander disease. J Neurosci 34:6448-58
McCluskey, Leo F; Geser, Felix; Elman, Lauren B et al. (2014) Atypical Alzheimer's disease in an elderly United States resident with amyotrophic lateral sclerosis and pathological tau in spinal motor neurons. Amyotroph Lateral Scler Frontotemporal Degener 15:466-72
Bit-Ivan, Esther N; Suh, Eunran; Shim, Hyung-Sub et al. (2014) A novel GRN mutation (GRN c.708+6_+9delTGAG) in frontotemporal lobar degeneration with TDP-43-positive inclusions: clinicopathologic report of 6 cases. J Neuropathol Exp Neurol 73:467-73

Showing the most recent 10 out of 333 publications