Tubulin transforms Tau and α-synuclein condensates from pathological to physiological

https://doi.org/10.1101/2025.02.27.640500

 

Abstract

Proteins phase-separate to form condensates that partition and concentrate biomolecules into membraneless compartments. These condensates can exhibit dichotomous behaviors in biology by supporting cellular physiology or instigating pathological protein aggregation. Tau and α- synuclein (αSyn) are neuronal proteins that form heterotypic (Tau:αSyn) condensates associated with both physiological and pathological processes. Tau and αSyn functionally regulate microtubules, but are also known to misfold and co-deposit in aggregates linked to various neurodegenerative diseases, which highlights the paradoxically ambivalent effect of Tau:αSyn condensation in health and disease. Here, we show that tubulin modulates Tau:αSyn condensates by promoting microtubule interactions, competitively inhibiting the formation of homotypic and heterotypic pathological oligomers. In the absence of tubulin, Tau-driven protein condensation accelerates the formation of toxic Tau:αSyn heterodimers and amyloid fibrils. However, tubulin partitioning into Tau:αSyn condensates modulates protein interactions, promotes microtubule polymerization, and prevents Tau and αSyn oligomerization and aggregation. We distinguished distinct Tau and αSyn structural states adopted in tubulin-absent (pathological) and tubulin-rich (physiological) condensates, correlating compact conformations with aggregation and extended conformations with function. Furthermore, using various neuronal cell models, we showed that loss of stable microtubules, which occurs in Alzheimer’s disease and Parkinsons disease patients results in pathological oligomer formation and loss of neurites, and that functional condensation using an inducible optogenetic Tau construct resulted in microtubule stablization. Our results identify that tubulin is a critical modulator in switching Tau:αSyn pathological condensates to physiological, mechanistically relating the loss of stable microtubules with disease progression. Tubulin restoration strategies and Tau-mediated microtubule stabilization can be potential therapies targeting both Tau-specific and Tau/αSyn mixed pathologies.

 

요약

1. Tau와 α-시뉴클레인(αSyn)이 이질적 응집체(heterotypic condensates)를 형성하는 과정 분석: Tau와 αSyn은 신경세포에서 LLPS(액체-액체 상분리)를 통해 응집체를 형성하며, 이는 신경퇴행성 질환과 연관될 수 있습니다.
2. 튜불린이 Tau:αSyn 응집체의 형성과 구조를 조절함을 발견: 튜불린이 존재할 경우 Tau와 αSyn의 상호작용이 변화하며, 병리적 응집체(amyloid fibrils) 대신 미세소관(microtubules) 형성이 촉진됨을 확인하였습니다.
3. 튜불린의 부족이 신경퇴행성 질환의 병리적 응집체 형성을 촉진함: 튜불린이 부족할 경우, Tau와 αSyn의 응집이 증가하고, 아밀로이드 섬유 형성이 가속화됨을 보여주었습니다.
4. 광유전학적(optogenetic) Tau 제어를 통해 미세소관 안정성을 조절할 수 있음: 광활성화(blue-light activation)를 통해 Tau가 미세소관을 안정화하는 능력을 가짐을 실험적으로 증명하였습니다.
5. 튜불린 회복이 신경퇴행성 질환 치료의 가능성을 제시함: 연구 결과를 바탕으로, 튜불린 수준을 복원하는 전략이 Tau 및 αSyn 관련 질환(알츠하이머병, 파킨슨병)의 치료법이 될 가능성을 제안하였습니다.