Why Does the Transport of Molecules into the Nucleus Fail in Alzheimer?

We aim to understand how the neuronal protein Tau interferes with the transport of biomolecules across the nuclear envelope in Alzheimer’s disease. In Alzheimer’s disease, Tau proteins can interact with entities of the nuclear envelope leading to impaired molecular transport in and out of the nucleus. In this project we aim to identify proteins that interact with Tau in the nuclear envelope. Tau can for example bind to proteins in nuclear pores, named nucleoporins, and we will try to identify which parts of Tau are relevant for this binding. Having identified the aberrant interactions of Tau with the nuclear envelope, we aim to find compounds and genetic modifiers that can prevent them and thus rescue the downstream transport deficits.

In the last years, nuclear transport deficits have been identified in different neurodegenerative protein aggregation diseases. In Alzheimer’s disease, the axonal microtubule binding protein Tau accumulates in the somatodendritic compartment, whereby it gains access to the nuclear envelope and the embedded nuclear pore complexes, which are essential for the transport of proteins and RNA in and out of the nucleus. The aberrant interactions of Tau with nucleopore proteins, nucleoporins (Nups), induce a pronounced impairment in nucleocytoplasmic transport processes, whereby two mechanisms seem to play a role: direct binding of soluble tau to Nups in pore complexes, and co-aggregation of Nups with Tau in cytosolic neurofibrillary tangles, the hallmark Tau pathological change in Alzheimer’s brains. In both scenarios, the molecular mechanism of Tau:Nup interactions are unknown.
To understand how Tau interacts with and impairs nuclear pores, we will determine the Tau:Nup interactome in human neurons and correlate our findings with the status in human AD brains. Furthermore, we will determine molecular details of Tau:Nup interactions using different protein biophysical methods. Last but not least, we will use cells equipped with a nuclear transport reporter to screen for small molecule and and genetic modifiers of Tau-induced nuclear transport deficits. Our find can directly deliver potential therapeutic targets for the treatments of nuclear transport deficits in AD and tauopathies.

In this work we follow up on recent findings that identified aberrant interactions of Tau proteins with the nerve cell nucleus. We use a unique combination of proteomics, cell biology, protein biophysics and gene editing to understand how Tau proteins can disable transport across the nuclear envelope and how we could rescue these impairments in disease.

We hope to understand Tau protein inflicted nuclear transport deficits in Alzheimer’s disease and other tauopathies and develop an approach for interference with this pathological process.