Frontotemporal dementia is a fatal neurodegenerative disease that results in progressive decline in behavior, executive function, and language. Currently, there are no effective treatments. Recent advances, however, have led to a greater understanding of the most common pathological form of the disease, called frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). In 2006, the major protein in the hallmark ubiquitinated inclusions of FTLD-U was identified as TAR DMA binding protein 43 (TDP-43). The function of TDP-43 is largely unknown. However, several lines of evidence indicate a role in the regulation of gene expression. TDP-43 binds DNA and RNA, regulating through these interactions the temporal and tissue-specific expression of some genes, as well as the splicing of others. Moreover, physiologic TDP-43 is nuclear, where it associates with heterogeneous ribonucleoproteins with well-known splicing activities. This research proposal is designed around the hypothesis that through aberrant activity of TDP-43, dysregulation of gene expression is a key disease mechanism in FTLD-U. Genome-wide approaches will be employed to evaluate this hypothesis. The following are the proposal's specific aims: 1. Obtain and analyze genome-wide expression profiles of FTLD-U at the mRNA and microRNA levels. 2. Identify DNA binding partners of TDP-43 in cell culture models and in FTLD-U using chromatin immunoprecipitation of TDP-43 followed by microarray analysis (ChlP-on-chip). 3. Characterize the relationship of specific microRNAs and TDP-43 to changes in mRNA expression. 4. Extend techniques developed in the study of FTLD-U to other diseases characterized by the accumulation of pathologic TDP-43.
Frontotemporal dementia is the second-most common cause of dementia in individuals under age 65. Understanding key genes dysregulated in this disease could lead to the development of targeted therapies.
|Brettschneider, Johannes; Arai, Kimihito; Del Tredici, Kelly et al. (2014) TDP-43 pathology and neuronal loss in amyotrophic lateral sclerosis spinal cord. Acta Neuropathol 128:423-37|
|Brettschneider, Johannes; Del Tredici, Kelly; Irwin, David J et al. (2014) Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD). Acta Neuropathol 127:423-439|
|Gallagher, Michael D; Suh, Eunran; Grossman, Murray et al. (2014) TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathol 127:407-18|
|Chahine, Lama M; Stern, Matthew B; Chen-Plotkin, Alice (2014) Blood-based biomarkers for Parkinson's disease. Parkinsonism Relat Disord 20 Suppl 1:S99-103|
|Toledo, Jon B; Van Deerlin, Vivianna M; Lee, Edward B et al. (2014) A platform for discovery: The University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Alzheimers Dement 10:477-84.e1|
|Busch, Johanna I; Martinez-Lage, Maria; Ashbridge, Emily et al. (2013) Expression of TMEM106B, the frontotemporal lobar degeneration-associated protein, in normal and diseased human brain. Acta Neuropathol Commun 1:36|
|Braak, Heiko; Brettschneider, Johannes; Ludolph, Albert C et al. (2013) Amyotrophic lateral sclerosis--a model of corticofugal axonal spread. Nat Rev Neurol 9:708-14|
|Wood, Elisabeth M; Falcone, Dana; Suh, Eunran et al. (2013) Development and validation of pedigree classification criteria for frontotemporal lobar degeneration. JAMA Neurol 70:1411-7|
|Brettschneider, Johannes; Del Tredici, Kelly; Toledo, Jon B et al. (2013) Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol 74:20-38|
|Qiang, Judy K; Wong, Yvette C; Siderowf, Andrew et al. (2013) Plasma apolipoprotein A1 as a biomarker for Parkinson disease. Ann Neurol 74:119-27|
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