Disease-specific tau polymorphs are associated with unique protein networks across proteinopathies
TL;DR
It is demonstrated that conformationally distinct tau polymorphs associate with disease-specific interaction networks across Alzheimer's disease, progressive supranuclear palsy, and dementia with Lewy bodies, providing molecular insight into tauopathy heterogeneity.
Abstract
Tau protein aggregates adopt distinct conformations across tauopathies, yet the protein interactions engaged by disease-specific polymorphs remain poorly characterized. Here, we demonstrate that conformationally distinct tau polymorphs associate with disease-specific interaction networks across Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). Interactome profiling of tau aggregates from PBS- and sarkosyl-soluble brain fractions identified 493 high-confidence interactors exhibiting remarkable disease specificity. As an exploratory feature discovery machine learning classification discriminated against diseases using as few as four to six protein features. AD tau selectively engaged glycolytic enzymes, TCA cycle components, and glutamate/GABA cycling machinery, with the astrocytic transporter SLC1A2 showing 27-fold enrichment. PSP tau exhibited extensive interactor depletion alongside selective proteasome enrichment, whereas DLB tau associated with neurogenesis modulators while depleting neuroinflammatory mediators. Interaction patterns were corroborated by parallel reaction monitoring mass spectrometry and proximity ligation assays and corresponded to disease-specific post-translational modification profiles. These findings show that tau polymorph conformations are associated with disease-specific interaction networks, providing molecular insight into tauopathy heterogeneity. Conformationally distinct tau aggregates arise across tauopathies, but the proteins they engage are unknown. This study links tau polymorphs from Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB) to interaction networks, offering insight into disease heterogeneity. Interactome profiling of tau aggregates from PBS- and sarkosyl-soluble AD, PSP and DLB postmortem brain identifies 493 high-confidence interactors with pronounced disease specificity. AD-tau selectively engages glycolytic enzymes, TCA-cycle components and glutamate/GABA-cycling machinery, with the astrocytic glutamate transporter SLC1A2 enriched 27-fold. PSP-tau shows broad interactor depletion alongside selective proteasome enrichment, whereas DLB-tau associates with neurogenesis-modulators while depleting neuroinflammatory mediators. Interaction patterns are corroborated by parallel reaction monitoring mass spectrometry and proximity ligation assays, and correspond to disease-specific tau post-translational modification profiles. Interactome profiling of tau aggregates from PBS- and sarkosyl-soluble AD, PSP and DLB postmortem brain identifies 493 high-confidence interactors with pronounced disease specificity. AD-tau selectively engages glycolytic enzymes, TCA-cycle components and glutamate/GABA-cycling machinery, with the astrocytic glutamate transporter SLC1A2 enriched 27-fold. PSP-tau shows broad interactor depletion alongside selective proteasome enrichment, whereas DLB-tau associates with neurogenesis-modulators while depleting neuroinflammatory mediators. Interaction patterns are corroborated by parallel reaction monitoring mass spectrometry and proximity ligation assays, and correspond to disease-specific tau post-translational modification profiles. Interactome profiling of tau aggregates from postmortem brain of Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB) provides new insights into disease heterogeneity.
