YTHDC1 functions as a molecular chaperone to suppress ALS-Linked hnRNPA1 mutants from aggregation

ABSTRACT: Proteostasis failure underlies many neurodegenerative disorders (NDs), yet ATP-independent chaperone mechanisms in NDs remain incompletely defined. Here, we identify the N6-methyladenosine (m6A) binding protein YTHDC1 as an ATP-independent molecular chaperone whose activity is mediated by a highly acidic polyD/E segment. We demonstrate that YTHDC1 prevents heat-induced misfolding and aggregation, unfolds kinetically trapped substrates, and resolubilizes pre-formed aggregates. Depletion polyD/E abolishes these activities and reduces condensate fluidity. The chaperone function of YTHDC1 is independent of m6A recognition, as YTHDC1 aromatic-cage mutants retain the chaperone activities. We identify that hnRNPA1, an RNA binding protein, is one of the clients of YTHDC1. Focusing on the ALS-linked hnRNPA1, YTHDC1 maintains liquid-like condensates, delays fibrillization of disease mutants, and limits stress-granule sequestration, thereby preserving its normal cellular function and mitigating synaptic atrophy elicited by pathological hnRNPA1 in primary neurons. These findings reveal a novel function of YTHDC1 in proteostasis and suggest that enhancing its chaperone activity could offer a promising therapeutic strategy for counteracting the effects of protein aggregation in NDs.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: Kang Ren  

LAB HEAD: Liangqian Huang

PROVIDER: PXD073870 | Pride | 2026-08-22

REPOSITORIES: Pride