This study aims to investigate a novel mechanistic converging pathway for Tau and TDP43 in regulating ER-microtubule dynamics in Frontotemporal Dementia.

Frontotemporal Dementia (FTD) is a major neurodegenerative disease and the most common cause of early-onset dementia. FTD is characterized by distinct clinical syndromes such as dementia, personality changes, and language difficulties, and is pathologically marked by cytoplasmic TDP-43 or Tau protein aggregate. And genetic mutations in either TDP-43 or Tau can also cause FTD. However, while TDP-43 and Tau have distinct cellular functions, how TDP-43 and Tau converge in FTD to cause dementia still remains unclear.

The endoplasmic reticulum (ER) forms highly specialized contacts with microtubules at hubs known as ER-microtubule contact sites, and can be tethered by STIM1 on the ER. However, whether ER-microtubule contact sites are misregulated in FTD is still not known, and whether mutant TDP-43 and Tau disrupt ER-microtubule contacts underlying FTD has never been studied.

We used advanced Super-Resolution live microscopy of human cells to identify how Frontotemporal Dementia mutations in TDP-43 and Tau modulate ER-microtubule contact tethering. We further elucidated the mechanisms underlying ER-microtubule contact misregulation in FTD.

Using live Super-Resolution Lattice SIM2 microscopy, we demonstrate that FTD-linked TDP-43 mutant (M337V) and Tau mutant (P301L) significantly decrease ER-microtubule contact site tethering by STIM1. In addition, both FTD-linked mutant TDP-43 and Tau induce phosphatase cytoplasmic granule formation, and we further show that misregulated phosphatase dynamics may lead to altered ER-microtubule contact tethering in FTD. 

FTD disease-associated mutations in TDP-43 and Tau directly impair ER-microtubule tethering by STIM1, leading to destabilization of ER-microtubule contacts potentially by altering phosphatase dynamics. As ER-microtubule contacts are important for microtubule polymerization that supports dendritic spine stability and memory, this may be an important molecular mechanism underlying dementia in FTD.