Hsp70 chaperones TDP-43 in dynamic, liquid-like phase and prevents it from amyloid aggregation

Dear Editor,

TAR DNA-binding protein 43 kDa (TDP-43) undergoes liquid–liquid phase separation (LLPS) and forms reversible, cytoprotective nuclear bodies (NBs) under stress.¹ Abnormal liquid-to-solid phase transition condenses TDP-43 into irreversible pathological fibril, which is associated with neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD).^2,3 However, the mechanisms by which cells maintain the highly aggregation-prone protein in the liquid-like phase and prevent TDP-43 NBs from aggregation under stressed conditions remain elusive. Molecular chaperones play a crucial role in maintaining protein homeostasis. Heat shock protein (Hsp) 70 can interact with TDP-43⁴ and increase of Hsp70 suppresses TDP-43-mediated toxicity in fly models.⁵ Importantly, ALS patients with TDP-43 aggregates exhibit significantly decreased Hsp70 levels,⁶ suggesting that Hsp70 maintains TDP-43 proteostasis and that its dysregulation may be involved in pathological aggregation of TDP-43 RNA–protein granules in ALS and related diseases.

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