Searching for a chaperone

A hallmark of amyotrophic lateral sclerosis is the presence of cytoplasmic aggregates that contain the essential nuclear protein TDP-43. Like many RNA- and DNA-binding proteins, TDP-43 naturally forms liquid droplets via phase separation, but it is unclear what normally prevents the transition into pathogenic aggregates. To identify potential TDP-43-interacting proteins, Lu et al. performed proximity labeling and quantitative mass spectrometry, identifying the chaperone HSPB1. When cells were stressed, HSPB1 interacted with TDP-43, chaperoning it into liquid droplets, then aided disassembly after stress removal. Through both in vitro assays and small interfering RNA–induced cellular depletion, the authors showed that without HSPB1, TDP-43 liquid droplets ‘aged’ into gel-like condensates and fibrils, irreversibly trapping the protein. During this ‘de-mixing’, the cytoplasmic condensates also recruited and trapped nuclear TDP-43, pushing the cells into a pathological state. Patients with amyotrophic lateral sclerosis that exhibited pathological TDP-43 aggregates were also confirmed as having lower levels of HSPB1, which demonstrates a clear link between TDP-43, HSPB1 and motor neuron health. Overall, this elegant study reveals the importance of careful coordination of protein condensates to prevent aggregation.

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