UCSF

Recently, mutations in TSC1 leading to haploinsufficiency have been linked to a novel, age-related tauopathy, unlike any other characterized tauopathy. However, TSC1 has been classically studied in the context of the neurodevelopmental disorder, tuberous sclerosis. Therefore, limited models and work exist exploring the full pathology of TSC1 haploinsufficiency induced mutations. Using TSC1 haploinsufficient cortical organoids, we interrogate the molecular changes caused by loss of TSC1 via biochemical, proteomic, and single-cell RNA sequencing methods. We show that TSC1 mutant cortical organoids model features of neurodegeneration including glutamatergic neuron loss with synapse damage, in addition to hallmarks of tuberous sclerosis like developmental delays and expansion of interneurons. Additionally, we employ RT-QuIC and EMBER analysis to characterize the novel tau species that arises from TSC mutations. In this work we provide evidence that TSC1 haploinsufficiency induces a unique seeding competent-tau conformation reminiscent of a CTE-like tau fold, but distinct from that of tau found in AD.