TY - JOUR
T1 - RNA induces unique tau strains and stabilizes Alzheimer's disease seeds
AU - Zwierzchowski-Zarate, Amy N.
AU - Mendoza-Oliva, Aydé
AU - Kashmer, Omar M.
AU - Collazo-Lopez, Josue E.
AU - White, Charles L.
AU - Diamond, Marc I.
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2022/8
Y1 - 2022/8
N2 - Tau aggregation underlies neurodegenerative tauopathies, and transcellular propagation of tau assemblies of unique structure, i.e., strains, may underlie the diversity of these disorders. Polyanions have been reported to induce tau aggregation in vitro, but the precise trigger to convert tau from an inert to a seed-competent form in disease states is unknown. RNA triggers tau fibril formation in vitro and has been observed to associate with neurofibrillary tangles in human brain. Here, we have tested whether RNA exerts sequence-specific effects on tau assembly and strain formation. We found that three RNA homopolymers, polyA, polyU, and polyC, all bound tau, but only polyA RNA triggered seed and fibril formation. In addition, polyA:tau seeds and fibrils were sensitive to RNase. We also observed that the origin of the RNA influenced the ability of tau to adopt a structure that would form stable strains. Human RNA potently induced tau seed formation and created tau conformations that preferentially formed stable strains in a HEK293T cell model, whereas RNA from other sources, or heparin, produced strains that were not stably maintained in cultured cells. Finally, we found that soluble, but not insoluble seeds from Alzheimer's disease brain were also sensitive to RNase. We conclude that human RNA specifically induces formation of stable tau strains and may trigger the formation of dominant pathological assemblies that propagate in Alzheimer's disease and possibly other tauopathies.
AB - Tau aggregation underlies neurodegenerative tauopathies, and transcellular propagation of tau assemblies of unique structure, i.e., strains, may underlie the diversity of these disorders. Polyanions have been reported to induce tau aggregation in vitro, but the precise trigger to convert tau from an inert to a seed-competent form in disease states is unknown. RNA triggers tau fibril formation in vitro and has been observed to associate with neurofibrillary tangles in human brain. Here, we have tested whether RNA exerts sequence-specific effects on tau assembly and strain formation. We found that three RNA homopolymers, polyA, polyU, and polyC, all bound tau, but only polyA RNA triggered seed and fibril formation. In addition, polyA:tau seeds and fibrils were sensitive to RNase. We also observed that the origin of the RNA influenced the ability of tau to adopt a structure that would form stable strains. Human RNA potently induced tau seed formation and created tau conformations that preferentially formed stable strains in a HEK293T cell model, whereas RNA from other sources, or heparin, produced strains that were not stably maintained in cultured cells. Finally, we found that soluble, but not insoluble seeds from Alzheimer's disease brain were also sensitive to RNase. We conclude that human RNA specifically induces formation of stable tau strains and may trigger the formation of dominant pathological assemblies that propagate in Alzheimer's disease and possibly other tauopathies.
KW - Alzheimer disease
KW - RNA
KW - fibril
KW - neurodegenerative disease
KW - oligomer
KW - protein self-assembly
KW - tau
KW - tauopathy
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U2 - 10.1016/j.jbc.2022.102132
DO - 10.1016/j.jbc.2022.102132
M3 - Article
C2 - 35700826
AN - SCOPUS:85135787411
SN - 0021-9258
VL - 298
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 8
M1 - 102132
ER -