Identification\nof a Hidden, Highly Aggregation-Prone\nIntermediate of Full-Length TDP-43 That Triggers its Misfolding and\nAmyloid Aggregation

In cells, TDP-43 is a crucial protein that can form harmful\namyloid\naggregates linked to fatal and incurable human neurodegenerative disorders.\nNormally, TDP-43 exists in a smaller soluble native state that prevents\naggregation. However, aging and stress can destabilize this native\nstate, leading to the formation of disease-causing amyloid aggregates\nvia the formation of partially unfolded, high-energy intermediates\nwith a greater tendency to aggregate. These intermediates are crucial\nin the early stages of amyloid formation and are challenging to study\ndue to their low stability. Understanding the structure of these early\naggregation-prone states of TDP-43 is essential for designing effective\ntreatments for TDP-43 proteinopathies. Targeting these initial intermediates\ncould be more effective than focusing on fully formed amyloid aggregates.\nBy disrupting the aggregation process at this early stage, we may\nbe able to prevent the progression of diseases related to TDP-43 aggregation.\nHence, we decided to uncover the hidden, high-energy intermediates\nin equilibrium with the native states of TDP-43 by modulating the\nthermodynamic stability of the soluble native dimer (N form) and monomeric\nmolten globular state (MG form) of full-length TDP-43. The thermodynamic\nmodulation performed in the current study successfully revealed the\nhighly aggregation-prone intermediate of full-length TDP-43, i.e.,\nPUF. Moreover, we observed that along with high aggregation propensity,\nthe aggregation kinetics and mechanisms of PUF differ from previously\nidentified intermediates of full-length TDP-43 (the MG and I forms).\nThe information regarding the initial aggregation-prone state of full-length\nTDP-43 could lead to therapies for amyloid diseases by halting early\nprotein aggregation.