Isoform specific mediation of TAU toxicity and differential neuronal vulnerability

• Applicant: Dr. Hans Zempel
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Experimental Models for the Understanding of Nervous System Diseases ; Human Genetics ; Molecular Biology and Physiology of Neurons and Glial Cells ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 503490891

Tauopathies are mainly genetic or familiar neurological diseases, characterized by adult onset and severe cognitive decline. These diseases impose a tremendous burden on patients, their families, caregivers and society. There are no treatments that can stop or reverse the disease progression.The histopathological and molecular correlate of the declining cognitive functions of these forms of dementia are loss of synapses and somatic accumulations of the protein TAU. This TAU pathology spreads in a defined fashion through the brain and affects different brain regions at different stages, hinting to differential vulnerability of neuronal subpopulations. Central nervous system TAU is composed of 6 differentially expressed splice-variants. Changes in the isoform ratio alone are sufficient to cause dementia. Our preliminary data show that specific isoforms can mediate TAU toxicity. TAU isoforms are differentially localized in axons and dendrites, but this sorting pattern is impaired in disease. The events leading to TAU missorting remain enigmatic.Here we aim to identify the isoform responsible for mediating TAU toxicity, and cell types particular susceptible to TAU pathology. We use disease-relevant neurons expressing all 6 TAU isoforms (in contrast to only 3 mature mouse Tau-isoforms) to investigate TAU isoform sorting, missorting, differential contribution to TAU and downstream pathology, and the identification and therapeutic suppression of the toxicity-mediating TAU isoform(s). We will use neurons derived from induced pluripotent stem cells (iPSCs; differentiatable both in homogenous glutamatergic neurons and heterogenous neuronal cultures) and TAU-humanized transgenic mice expressing all human 6 human TAU isoforms. With our state of the art cell biology & biochemistry laboratories at the CMMC and access to core facilities of the CECAD/CCG, we will use advanced microscopy, biochemistry and transcriptomics. Using life-imaging and immunofluorescence microscopy, we will study the cellular behavior of the different Tau isoforms (i.e. expression ratio, distribution, turnover time), their influence on the cytoskeleton, axodendritic plasticity and synapse formation, and identify the isoform responsible for mediating TAU toxicity. Via state-of-the-art genetic knockout techniques/strategies, antibody mediated suppression and RNAi-based knockdown we will suppress individual TAU isoforms. Using single-cell-RNA-sequencing and cluster analysis, we will identify i) neuronal subpopulations susceptible to TAU toxicity and, ii) factors facilitating or preventing TAU pathology. Understanding basic TAU physiology is crucial to develop targeted TAU-based therapies. Granting help from the DFG/GRC, I am confident to contribute significantly to the elucidation of fundamental pathomechanisms of genetic tauopathies and related neurodegenerative diseases, and develop novel therapeutic strategies.

• DFG Programme: Research Grants