? PROJECT 1 FTLD-tau exhibits imbalanced tau proteostasis (intra- and inter-cellar) and neuronal dysfunction. However, little is known about how the accumulation and spread of pathogenic tau could occur, and how it could affect neuronal and synaptic functions. As an integral part of the Center, project 1 (P1)'s objective is to dissect mechanisms underlying aberrant neuronal activity and tau distribution in FTD. We combine unbiased and hypothesis-driven approaches, which are extremely powerful but cannot be achieved without the structure of the Center. We propose three Specific Aims.
In Aim 1, we will define FTD mutations-induced aberrant tau post-translational modifications (PTMs) and dissect how acetylation stimulates tau release with P3.
Aim 1 will also be complemented by transcriptome analyses of the FTD mutation effects in P2.
In Aim 2, we will determine how FTLD-tau alters neuronal activity and activity-dependent tau release. We will expand on our preliminary study that V337M human neurons exhibit hyperexcitability with impaired homeostatic regulation of axon initial segment (AIS). We will systematically compare neuronal and synaptic activity in isogenic FTD mutant and control lines by whole-cell recordings. Working with mass-spec (MS) core, we will also dissect the mechanism underlying the activity-dependent tau release by dissecting tau interactome in response to high KCL (MS core). CRISPRi/a will then be performed to examine how modulating hits from interactome study would affect activity-dependent tau release (CRISPR core).
Aim 2 in P1 will be complemented by P2, which correlates neuronal activity with transcriptome, and P3, which examines the crosstalk between neuronal activity and tau degradation pathways.
In Aim 3, we will determine how FTD mutations affect pathogenic tau seeding. Pathogenic seeding is a key feature in tauopathy, but little is known about its mechanisms and functional outcome. We will compare neuronal and synaptic activity in receiving human neurons positive or negative for FRET signal resulting from tau oligomerization. To dissect the mechanisms mediating pathogenic seeding, we will compare the proteome associated with internalized mutant or WT tau seeds in human neurons (MS core). Proteins selectively linked with mutant tau will be prioritized as potential hits. Working with CRISPR core, we will inhibit/activate selected genes from the seeding proteome, and measure the outcome by FRET signal and whole-cell recordings. The proteomic approach in Aim 3 will be complemented by the genome-wide screening to identify pathways in internalization using unbiased approach (P2 and CRISPR core). Together with P2 and P3, P1 will contribute to our overall vision of dissecting the crosstalk between tau proteostasis imbalance and neuronal dysfunction.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
New York
United States
Zip Code
Paulo, Esther; Wu, Dongmei; Wang, Yangmeng et al. (2018) Sympathetic inputs regulate adaptive thermogenesis in brown adipose tissue through cAMP-Salt inducible kinase axis. Sci Rep 8:11001
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

Showing the most recent 10 out of 15 publications