This proposal investigates a novel mechanism for the misfolding and aggregation of microtubule associated protein tau (MAPT), which we hypothesize provides an unrecognized but major aspect of the pathophysiology of tauopathies, such as Alzheimer's disease (AD). We have recently identified a new type of molecular pathology in AD that derives from the aggregation of RNA binding proteins, forming RNA-protein complexes that include stress granules. These stress granules progressively accumulate in the brains of transgenic models of tauopathy, as well as massively accumulate in subjects with AD and FTDP-17. The genesis of this research comes from the simple observations that 1) RNA binding proteins form RNA granules through a striking property of reversible aggregation, which is under physiological regulation, and 2) MAPT binds to some RNA binding proteins, including TIA-1. RNA granules consolidate transcripts for transport, storage and/or degradation. Our results suggest that TIA-1 stimulates phosphorylation and misfolding of MAPT, and that MAPT stimulates formation of TIA-1 positive stress granules; the association of MAPT with stress granules reduces its degradation and appears to stabilize insoluble MAPT. The chronic nature of AD might lead to excessive formation of stress granules and aggregation of MAPT, contributing to neurodegeneration. We hypothesize that MAPT and RNA binding proteins exhibit bidirectional regulation. MAPT promotes the formation and stability of RNA granules, including stress granules. Conversely, RNA binding proteins and the translational signaling cascade stimulate the phosphorylation, and misfolding of MAPT. This hypothesis will be studied in the context of three aims:
Aim 1 will determine the mechanisms by which TIA-1 interacts with MAPT. We will use structural studies, imaging and mass spectroscopy to highlight key changes in discover key binding proteins.
Aim 2 will determine the role of MAPT in neuronal RNA granule biology, including stress granules.
This aim will explore this biology using live cell imaging to explore RNA granule dynamics under basal and stress conditions and will examine whether MAPT modulates the types of transcripts associated with particular RNA granules/ stress granules (using iCLIP). Finally, Aim 3 will determine whether stress granule/RNA translation pathways regulate MAPT-mediated neurodegeneration in vivo.
This aim will focus on the RNA binding proteins used in our preliminary studies (e.g., TIA-1) as well as the novel MAPT/ stress granule components identified by mass spectroscopy.
|Apicco, Daniel J; Ash, Peter E A; Maziuk, Brandon et al. (2018) Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo. Nat Neurosci 21:72-80|
|Boeynaems, Steven; Alberti, Simon; Fawzi, Nicolas L et al. (2018) Protein Phase Separation: A New Phase in Cell Biology. Trends Cell Biol 28:420-435|
|Li, Dan; Wang, Lei; Maziuk, Brandon F et al. (2018) Directed evolution of a picomolar-affinity, high-specificity antibody targeting phosphorylated tau. J Biol Chem 293:12081-12094|
|Ruan, Qiu T; Yazdani, Neema; Beierle, Jacob A et al. (2018) Changes in neuronal immunofluorescence in the C- versus N-terminal domains of hnRNP H following D1 dopamine receptor activation. Neurosci Lett 684:109-114|
|Ash, Peter E A; Stanford, Elizabeth A; Al Abdulatif, Ali et al. (2017) Dioxins and related environmental contaminants increase TDP-43 levels. Mol Neurodegener 12:35|
|Zhu, Haihao; Xue, Xiehua; Wang, Erming et al. (2017) Amylin receptor ligands reduce the pathological cascade of Alzheimer's disease. Neuropharmacology 119:170-181|
|Wolozin, Benjamin; Sotiropoulos, Ioannis (2017) Dendritic TAU-telidge. EBioMedicine 20:3-4|
|Russo, Arianna; Scardigli, Raffaella; La Regina, Federico et al. (2017) Increased cytoplasmic TDP-43 reduces global protein synthesis by interacting with RACK1 on polyribosomes. Hum Mol Genet 26:1407-1418|
|Sindi, Shireen; Ngandu, Tiia; Hovatta, Iiris et al. (2017) Baseline Telomere Length and Effects of a Multidomain Lifestyle Intervention on Cognition: The FINGER Randomized Controlled Trial. J Alzheimers Dis 59:1459-1470|
|Maziuk, Brandon; Ballance, Heather I; Wolozin, Benjamin (2017) Dysregulation of RNA Binding Protein Aggregation in Neurodegenerative Disorders. Front Mol Neurosci 10:89|
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