Biomolecular Tau condensation is linked to Tau accumulation at the nuclear envelope

Abstract

Biomolecular condensation of the neuronal microtubule-associated protein Tau (MAPT) can be induced by coacervation with polyanions like RNA, or by molecular crowding. Tau condensates have been linked to both functional microtubule binding and pathological aggregation in neurodegenerative diseases. We find that molecular crowding and coacervation with RNA, likely coexisting in the cytosol, synergize to enable Tau condensation at physiological buffer conditions and produce condensates with a strong affinity to charged surfaces. During condensate-mediated microtubule polymerization, this synergy enhances bundling and spatially arranges microtubules. We further show that different Tau condensates efficiently induce pathological Tau in cells, including small accumulations at the nuclear envelope that correlate with nucleocytoplasmic transport deficits. Fluorescent lifetime imaging reveals different molecular packing densities of Tau in cellular accumulations, and a condensate-like density for nuclear envelope Tau. These findings suggest that a complex interplay between interaction partners, post-translational modifications, and molecular crowding regulates the formation and function of Tau condensates. Conditions leading to prolonged existence of Tau condensates may induce the formation of seeding-competent Tau and lead to distinct cellular Tau accumulations.

Nuclear translocation of LINE-1 encoded ORF1p alters nuclear envelope integrity and disrupts nucleocytoplasmic transport in human neurons

“…Recent studies have shown that aggregated proteins such as Tau 83,122 , mutant Huntingtin 90 and C9orf72 poly-GA proteins 58 can target the NE and alter its integrity and function. Our data suggests that ORF1p might have a pathogenic action similar to ND-linked proteins by perturbing nuclear integrity.…”

“…Recent studies have shown that aggregated proteins such as Tau 71,114 , mutant Huntingtin 81 and C9ORF72 poly(GA) 49 can target the NE and alter its integrity and function.…”