Project - Identification of the phosphorylated tau interactome in frontotemporal dementia
Research Project Abstract
Tau is the central pathological protein in more than 20 types of neurodegenerative disease, which are collectively called tauopathies. Despite the known central role of tau in all these diseases, our current understanding about how tau causes toxicity and neurodegeneration is limited. The aim of this project is to identify all proteins that interact with pathological tau in different types of tauopathy (Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration and Pick’s disease). To do this we will perform co-immunoprecipitation to pull down pathological tau from human brain tissue samples, which we will then analyse using proteomics to identify all proteins that interact with pathological tau. Our study will provide novel insight into the different ways that tau causes toxicity in these diseases. This project is funded by the Brain & Mind Centre, University of Sydney (2020).
Challenges within the field
Challenge 1: We don’t know how tau causes neurodegeneration and dementia. In this project we will provide novel insight into how tau contributes to disease in multiple different types of tauopathies by simultaneously quantifying hundreds of proteins that interact with pathological tau in human brain tissue samples.
Challenge 2: We don’t yet know why tau causes different types of tauopathy. Our direct comparison of four major types of tauopathy will allow us to identify proteins that tau uniquely interact with in each disease, which will provide insight into why tau causes multiple different diseases
Research Project Description
Aim 1: Identify proteins that interact with pathological tau in different types of tauopathy. We will use co-immunoprecipitation to pull down pathological, phosphorylated tau from human brain tissue samples from cases of Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration and Pick’s disease. We will then use mass spectrometry to identify all proteins that interact with pathological tau in these diseases. We will then compare these data to identify similarities and differences between different tauopathies.
Aim 2: Validation and mechanistic studies for novel proteins that show a particularly strong interaction with pathological tau. We will validate our findings using multiplexed fluorescent immunohistochemistry to confirm that proteins identified by mass spectrometry co-localize with tau aggregates. We will then perform mechanistic cell culture studies to determine whether these interactions accelerate tau aggregation and cell death.
- To identify how tau causes toxicity in different diseases
- Identify new potential drug targets and biomarkers for frontotemporal dementia and Alzheimer’s disease
- Generate the first comprehensive database of proteins that interact with pathological tau.
Key Publications from this project
Pires G, McElligott S, Drusinsky S, Halliday G, Potier MC, Wisniewski T, Drummond E (2019) Secernin-1 is a novel phosphorylated tau binding protein that accumulates in Alzheimer's disease and not in other tauopathies. Acta Neuropathological Communications, 7(1):195
Infographic / Medical Diagram / Scientific Diagram / Picture
We have identified 125 proteins that interact with pathological tau in Alzheimer’s disease human brain tissue, which are new potential drug targets for Alzheimer’s disease (and potentially other tauopathies).