Project 3: Autophagy dysfunction and neuronal activity in FTD Ana Maria Cuervo SUMMARY This proposal investigates the interplay between pathogenic forms of tau and selective forms of autophagy in the context of frontotemporal dementia (FTD). We will coordinate the activities of this project with those of Project 1 and Project 2 to test our working hypothesis that tau-mediated toxicity in the autophagic pathways underlie the basis for the altered tau proteostasis and functional alterations observed in FTD-affected neurons. Project 3 will use cutting edge proteomics (MS Core) and genetics (CRISPR Core) in iPSC-derived neurons to investigate: 1) effect of pathogenic intra- and extracellular tau in the activity of three different forms of selective autophagy; 2) consequences of blockage of each of these forms of autophagy on neuronal activity and tau uptake. Project 3 will also utilize postmortem frozen human brain tissue from controls and FTD-tau patients (Human Core) to identify 3) changes in the properties of tau associated with autophagic compartments in control and patient brains. Assisted by the CRISPR Core, we will modulate levels of differentially tau- interacting proteins and address the effect of this intervention on autophagy and neuronal activity. Integration of data (Data Core) generated by this project with that from the other two projects in the Center will allow us to elucidate the contribution of tau toxicity on the autophagic system to the neuronal activity imbalance observed in FTD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54NS100717-04
Application #
9791005
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Min, Sang-Won; Sohn, Peter Dongmin; Li, Yaqiao et al. (2018) SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy. J Neurosci 38:3680-3688
Rauch, Jennifer N; Chen, John J; Sorum, Alexander W et al. (2018) Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs). Sci Rep 8:6382
Masand, Ruchi; Paulo, Esther; Wu, Dongmei et al. (2018) Proteome Imbalance of Mitochondrial Electron Transport Chain in Brown Adipocytes Leads to Metabolic Benefits. Cell Metab 27:616-629.e4
Tekirdag, Kumsal; Cuervo, Ana Maria (2018) Chaperone-mediated autophagy and endosomal microautophagy: Joint by a chaperone. J Biol Chem 293:5414-5424
Theofilas, Panos; Ehrenberg, Alexander J; Nguy, Austin et al. (2018) Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer's disease Braak stages: a quantitative study in humans. Neurobiol Aging 61:1-12
Kaushik, Susmita; Cuervo, Ana Maria (2018) The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol 19:365-381
Kampmann, Martin (2018) CRISPRi and CRISPRa Screens in Mammalian Cells for Precision Biology and Medicine. ACS Chem Biol 13:406-416
Nowakowski, Tomasz J; Rani, Neha; Golkaram, Mahdi et al. (2018) Regulation of cell-type-specific transcriptomes by microRNA networks during human brain development. Nat Neurosci 21:1784-1792
Martinez-Losa, Magdalena; Tracy, Tara E; Ma, Keran et al. (2018) Nav1.1-Overexpressing Interneuron Transplants Restore Brain Rhythms and Cognition in a Mouse Model of Alzheimer's Disease. Neuron 98:75-89.e5
Mavor, David; Barlow, Kyle A; Asarnow, Daniel et al. (2018) Extending chemical perturbations of the ubiquitin fitness landscape in a classroom setting reveals new constraints on sequence tolerance. Biol Open 7:

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