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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG017586-14
Application #
8645560
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
14
Fiscal Year
2014
Total Cost
$278,219
Indirect Cost
$83,468
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Irwin, David J; Xie, Sharon X; Coughlin, David et al. (2018) CSF tau and ?-amyloid predict cerebral synucleinopathy in autopsied Lewy body disorders. Neurology 90:e1038-e1046
Ferraro, Pilar M; Jester, Charles; Olm, Christopher A et al. (2018) Perfusion alterations converge with patterns of pathological spread in transactive response DNA-binding protein 43 proteinopathies. Neurobiol Aging 68:85-92
Massimo, Lauren; Xie, Sharon X; Rennert, Lior et al. (2018) Occupational attainment influences longitudinal decline in behavioral variant frontotemporal degeneration. Brain Imaging Behav :
Spiller, Krista J; Restrepo, Clark R; Khan, Tahiyana et al. (2018) Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy. Nat Neurosci 21:329-340
Rey, Nolwen L; George, Sonia; Steiner, Jennifer A et al. (2018) Spread of aggregates after olfactory bulb injection of ?-synuclein fibrils is associated with early neuronal loss and is reduced long term. Acta Neuropathol 135:65-83
Irwin, David J; McMillan, Corey T; Xie, Sharon X et al. (2018) Asymmetry of post-mortem neuropathology in behavioural-variant frontotemporal dementia. Brain 141:288-301
Lewczuk, Piotr; Riederer, Peter; O'Bryant, Sid E et al. (2018) Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry. World J Biol Psychiatry 19:244-328
Phillips, Jeffrey S; Da Re, Fulvio; Dratch, Laynie et al. (2018) Neocortical origin and progression of gray matter atrophy in nonamnestic Alzheimer's disease. Neurobiol Aging 63:75-87
Kassubek, Jan; Müller, Hans-Peter; Del Tredici, Kelly et al. (2018) Longitudinal Diffusion Tensor Imaging Resembles Patterns of Pathology Progression in Behavioral Variant Frontotemporal Dementia (bvFTD). Front Aging Neurosci 10:47
Cousins, Katheryn A Q; Ash, Sharon; Grossman, Murray (2018) Production of verbs related to body movement in amyotrophic lateral sclerosis (ALS) and Parkinson's Disease (PD). Cortex 100:127-139

Showing the most recent 10 out of 593 publications