Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.16.154757v1?rss=1 Authors: Bachmann, S., Bell, M., Klimek, J., Zempel, H. Abstract: In the adult human brain, six isoforms of the microtubule-associated protein TAU are expressed, which result from alternative splicing of exons 2, 3 and 10 of the MAPT gene. These isoforms differ in the number of N-terminal inserts (0N, 1N, 2N) and C-terminal repeat domains (3R or 4R) and are differentially expressed depending on the brain region and developmental stage. Although all TAU isoforms can aggregate and form neurofibrillary tangles, some tauopathies, such as Pick's Disease and Progressive Supranuclear Palsy, are characterized by the accumulation of specific TAU isoforms. Many studies focused on the role of TAU in these diseases, however only few addressed isoform-specific functions of TAU in healthy and under pathological conditions. In this report, we investigated the subcellular localization of the human-specific TAU isoforms in primary mouse neurons. Our results show that 2N-TAU isoforms are particularly retained from axonal sorting and that axonal enrichment is independent from the number of repeat domains. Furthermore, we analyzed TAU isoform-specific effects on cell area and microtubule dynamics in SH-SY5Y neuroblastoma cells and observed a general reduction of cell size and an increase of microtubule counts in cells expressing 4R-TAU isoforms. Our study points out TAU isoform-specific effects that will be addressed in follow-up studies to unravel if and how TAU isoforms contribute to cellular functions in health and disease. Copy rights belong to original authors. Visit the link for more info