This Supplement proposal takes advantage of novel genetic model systems and bioinformatic approaches developed by two young investigators supported by the MDIBL COBRE P20 award (Comparative Biology of Tissue Repair, Regeneration and Aging; P20GM104318) and extends the impact of these approaches to solving the problems in Alzheimer?s disease (AD). Each of these studies proposes a pilot project that will allow the PI to seek competing support to pursue promising leads from the research proposed in this supplement request. COBRE Project 1 (Beck). Nuclei from AD neurons exhibit global mis-localization/degradation of nuclear lamin proteins and loss of heterochromatin marks both in human patients and animal models. Although these changes in chromatin architecture have been well characterized, the exact mechanism by which they contribute to degenerative changes in AD remains unknown. This proposal aims to determine how the disruption of nuclear chromatin architecture contributes to degenerative changes in AD. Our preliminary results demonstrate that, in normal young nuclei, only genes lacking CpG islands (CGI- genes) can reside within lamina-associated heterochromatin, when transcriptionally inactive. In this project, we will test the novel hypothesis that changes in chromatin architecture in AD cause mis-localization of CGI- genes that, in turn, triggers their uncontrolled expression in tissues/contexts where they should not be expressed. We will also examine whether CGI- gene mislocalization can be used as a diagnostic marker for AD in human clinical samples. COBRE Project 3 (Rollins). During AD, the association of Tau with the ribosome leads to its dysfunction. Such dysfunction is likely due to association of Tau with ribosomal protein 6 (RPS-6). This association coincides with the dephosphorylation of RPS-6, which is a potential mechanism by which Tau causes ribosome dysfunction and AD pathology. Using genetic models of RPS-6 phosphorylation we have generated in C.elegans, we will determine if phosphorylated RPS-6 reduces association of Tau with ribosomes. This will be accomplished by tracking the association of fluorescently tagged Tau with active ribosomes using fluorescent polysome profiling. Quantifying the association of Tau with the ribosome in RPS-6 mutants that cannot be phosphorylated or mimic constitutive phosphorylation will provide direct evidence that Tau association with the ribosome is controlled by RPS-6. Furthermore, measuring the lifespan and locomotion of the RPS-6 phospho-mutants in the presence of neuronally expressed Tau will determine whether phosphorylation of RPS-6 may alleviate symptoms of AD. Successful completion of these studies will show how nuclear structural changes leads to dysregulated gene expression in AD and support the development of new diagnostic markers of AD. This work will also clarify how Tau protein causes ribosome dysfunction in AD and support development of therapies targeting RPS-6 phosphorylation to slow the onset and progression Alzheimer?s disease.

Public Health Relevance

COBRE Project 1 (Beck) Nuclei from Alzheimer?s disease (AD) neurons exhibit global mis-localization/degradation of nuclear lamin proteins and loss of heterochromatin marks both in human patients and animal models. Understanding of how these structural changes contribute to AD-related pathophysiology is critical for developing intervention delaying the onset of AD-associated degenerative changes. COBRE Project 3 (Rollins) An early event in the progression of Alzheimer?s disease is dysfunction of the ribosome. This dysfunction has been attributed to the association of pathogenic Tau with the ribosome. Detailed understanding of the molecular mechanisms by which Tau associates leads to ribosome dysfunction is critical for developing therapies that slow the onset and progression Alzheimer?s disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
3P20GM104318-08S1
Application #
10123591
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Zhou, Yang
Project Start
2013-09-01
Project End
2023-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
8
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Mount Desert Island Biological Lab
Department
Type
DUNS #
077470003
City
Salsbury Cove
State
ME
Country
United States
Zip Code
04672
Lee, Bum-Kyu; Uprety, Nadima; Jang, Yu Jin et al. (2018) Fosl1 overexpression directly activates trophoblast-specific gene expression programs in embryonic stem cells. Stem Cell Res 26:95-102
Hampton, Thomas H; Jackson, Craig; Jung, Dawoon et al. (2018) Arsenic Reduces Gene Expression Response to Changing Salinity in Killifish. Environ Sci Technol 52:8811-8821
Yin, Viravuth P (2018) In Situ Detection of MicroRNA Expression with RNAscope Probes. Methods Mol Biol 1649:197-208
King, Benjamin L; Rosenstein, Michael C; Smith, Ashley M et al. (2018) RegenDbase: a comparative database of noncoding RNA regulation of tissue regeneration circuits across multiple taxa. NPJ Regen Med 3:10
Lavine, Kory J; Pinto, Alexander R; Epelman, Slava et al. (2018) The Macrophage in Cardiac Homeostasis and Disease: JACC Macrophage in CVD Series (Part 4). J Am Coll Cardiol 72:2213-2230
Yamada, Toshiki; Strange, Kevin (2018) Intracellular and extracellular loops of LRRC8 are essential for volume-regulated anion channel function. J Gen Physiol 150:1003-1015
Waldron, Ashley L; Schroder, Patricia A; Bourgon, Kelly L et al. (2018) Oxidative stress-dependent MMP-13 activity underlies glucose neurotoxicity. J Diabetes Complications 32:249-257
Beck, Samuel; Rhee, Catherine; Song, Jawon et al. (2018) Implications of CpG islands on chromosomal architectures and modes of global gene regulation. Nucleic Acids Res 46:4382-4391
Müller-Deile, Janina; Dannenberg, Jan; Schroder, Patricia et al. (2017) Podocytes regulate the glomerular basement membrane protein nephronectin by means of miR-378a-3p in glomerular diseases. Kidney Int 92:836-849
Rollins, Jarod A; Howard, Amber C; Dobbins, Sarah K et al. (2017) Assessing Health Span in Caenorhabditis elegans: Lessons From Short-Lived Mutants. J Gerontol A Biol Sci Med Sci 72:473-480

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