Identification of novel four repeat tauopathies through analysis of network vulnerability, tau structure and propagation. - Recently, significant progress in understanding tauopathies and how tau aggregates lead to neurodegeneration has been made by the description of the atomic structures of tau filaments from human brain. We have determined structures (resolutions of up to 2.7Å) of tau filaments from three individuals with typical progressive supranuclear palsy (PSP) and four with variant PSP. Clinically, typical cases of PSP are characterized by postural instability, supranuclear gaze palsy, behavioral and cognitive impairment, as well as bulbar symptoms. Neuropathologically, they are defined by abundant subcortical neurofibrillary tangles and neuropil threads (composed of 4R tau), together with tufted astrocytes and oligodendroglial coiled bodies. Atypical forms of PSP may be distinguished by differences in tau load in specific brain regions. In all cases of PSP, tau filaments are made of a single protofilament with an ordered core (PSP fold). During our study, we identified one case that had a different tau structure. Histologically, this case was also different from PSP because displayed abundant spherical, 4R tau immunoreactive, basophilic neuronal inclusions in frontal cortex and limbic structures. We named this disease ‘limbic-predominant neuronal inclusion body 4R tauopathy’ (LNT). LNT is a novel form of 4R tauopathy. The studies proposed in this MPI application are a logical continuation of this groundbreaking work. Cryo-EM analysis of an additional “PSP” case showed a different fold and histological profile from PSP (LNT-II). The overall goal of this application is to determine the prevalence of LNT in two large cohorts of PSP cases (Indiana and Toronto cohorts), characterize LNT-I and –II, two novel 4R tauopathies, and determine whether additional novel 4R entities can be identified that were previously diagnosed as PSP. We will also provide biochemical and structural validation of in vitro and in vivo models for mechanistic and therapeutic studies. In order to achieve our goals, our proposal has three specific aims. The first is to perform neuropathologic, genetic, and cryo-EM studies on a large cohort of PSP cases to characterize the prevalence and neuropathologic features of LNT and assess whether additional entities are present (and their tau structure). Second, we will identify the molecular changes occurring in tau in LNT-I/–II and characterize the seeding ability and potency of tau in vitro. Lastly, we will characterize the propagation of tau filaments from PSP and LNT-I/-II patients using custom microfluidic devices and a murine model. We will determine the atomic structure of seeded filaments from mice and assess whether tau conformers and their structural polymorphs are propagated true to their original form in vivo.
