Despite being a vital nuclear DNA and RNA binding protein regulating RNA transcription, splicing, transport and translation 7, modified TDP-43 forms cytoplasmic pathological inclusions of peculiar morphology under disease 5, 8. ![]() Prion-like spreading of aggregated TDP-43 structures plays key roles in the development of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and other major neurodegenerative diseases 1, 2, 3, 4, 5, 6. Our results show that metamorphism in the post-translationally modified TDP-43 prion-like domain encodes determinants that command mechanisms with major relevance in disease. Dismantling of the second helical element in TDP-43 prion-like domain by methionine sulfoxidation impacts phase separation and amyloid formation, abrogates chaperone recognition and alters phosphorylation by casein kinase-1δ. Significantly, while HSP70 and HSP90 chaperones promote TDP-43 phase separation, co-chaperones from the three classes of the large human HSP40 family (namely DNAJA2, DNAJB1, DNAJB4 and DNAJC7) show strikingly different effects on TDP-43 de-mixing. Here we show that chaperones and co-chaperones primarily recognize the structured elements in TDP-43´s prion-like domain. ![]() ![]() Despite the well-established protective roles for molecular chaperones against protein aggregation pathologies, knowledge on the determinants of chaperone recognition in disease-related prions is scarce. Aberrant TDP-43 aggregation arises upon phase de-mixing and transitions from liquid to solid states, following still unknown structural conversions which are primed by oxidative stress and chaperone inhibition. The RNA binding protein TDP-43 forms cytoplasmic inclusions via its C-terminal prion-like domain in several neurodegenerative diseases.
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