Objective: To enhance understanding of the molecular mechanisms underlying disease heterogeneity in Progressive supranuclear palsy (PSP)

Background: PSP is a 4R-tauopathy characterised by subcortical pathology in neurons, astrocytes and oligodendroglia associated with a broad range of clinical phenotypes. We hypothesized that heterogeneity in PSP is a consequence of the molecular diversity of tau between different patients and amongst different brain regions.

Method: We performed an extensive biochemical characterisation of the soluble, oligomeric tau species in 20 different brain regions from a cohort of 21 deeply phenotyped patients with PSP. This was complemented by detailed clinical, neuropathological and genetic data together with tau seeding amplification assays and proteomics.

Results: Our study has exposed a striking patient-to-patient heterogeneity in the soluble oligomeric tau species across the 20 brain regions examined. Tau seeding in motor cortex from all subjects revealed a strong correlation between the amount of soluble oligomeric tau species and the tau seeding capacity, strongly implicating these species in driving the seeding activity of tau in PSP. To identify factors that contribute to differences in seeding actvity, we quantified the amount of phosphorylated tau and evaluated the physical properties of tau in these diverse brain extracts using a protease-sensitivity digestion assay that differentiates protein conformations and correlated these measures with their tau seeding capacity. Finally, we have performed the first proteomic-wide profiling of the motor cortex in PSP and uncovered several mechanistic pathways that differentiate patients with high seeding activity and low and low seeding activity.

Conclusion: Our observations strongly suggest that that distinct molecular populations of tau contribute to the observed phenotypic differences in PSP. These data support the concept that individuals with PSP may have multiple molecular drivers of an otherwise common phenotype and emphasize the need for a novel molecular classification of PSP that will underpin the future development of personalized therapeutic approaches to curtail symptom progression.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/introducing-the-molecular-subtyping-of-progressive-supranuclear-palsy-a-proof-of-concept/