Abstract
The accumulation of amyloid Tau aggregates is implicated in Alzheimer's disease (AD) and other tauopathies. Molecular chaperones are known to maintain protein homeostasis. Here, we show that an ATP-dependent human chaperone system disassembles Tau fibrils in vitro. We found that this function is mediated by the core chaperone HSC70, assisted by specific cochaperones, in particular class B J-domain proteins and a heat shock protein 110 (Hsp110)-type nucleotide exchange factor (NEF). The Hsp70 disaggregation machinery processed recombinant fibrils assembled from all six Tau isoforms as well as Sarkosyl-resistant Tau aggregates extracted from cell cultures and human AD brain tissues, demonstrating the ability of the Hsp70 machinery to recognize a broad range of Tau aggregates. However, the chaperone activity released monomeric and small oligomeric Tau species, which induced the aggregation of self-propagating Tau conformers in a Tau cell culture model. We conclude that the activity of the Hsp70 disaggregation machinery is a double-edged sword, as it eliminates Tau amyloids at the cost of generating new seeds.
Highlights
The accumulation of amyloid Tau aggregates is implicated in Alzheimer’s disease (AD) and other tauopathies
The heat shock protein of 70 kDa (Hsp70) disaggregation machinery processed recombinant fibrils assembled from all six Tau isoforms as well as Sarkosyl-resistant Tau aggregates extracted from cell cultures and human AD brain tissues, demonstrating the ability of the Hsp70 machinery to recognize a broad range of Tau aggregates
We have previously shown that the human Hsp70 disaggregase comprised of HSC70, DNAJB1, and heat shock protein family A member 4 (HSPA4) can disassemble a-synuclein fibrils in vitro [21]
Summary
The accumulation of amyloid Tau aggregates is implicated in Alzheimer’s disease (AD) and other tauopathies. Recombinant fibrils of all six Tau isoforms, as well as Sarkosyl-resistant Tau aggregates extracted from a cell culture model or AD brain tissue, could be processed by this chaperone system, demonstrating that this chaperone machinery can disintegrate disease-relevant amyloids.
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