Abstract
The microtubule-associated protein, tau, is the major subunit of neurofibrillary tangles associated with neurodegenerative conditions, such as Alzheimer's disease. In the cell, however, tau aggregation can be prevented by a class of proteins known as molecular chaperones. While numerous chaperones are known to interact with tau, though, little is known regarding the mechanisms by which these prevent tau aggregation. Here, we describe the effects of ATP-independent Hsp40 chaperones, DNAJA2 and DNAJB1, on tau amyloid-fiber formation and compare these to the small heat shock protein HSPB1. We find that the chaperones play complementary roles, with each preventing tau aggregation differently and interacting with distinct sets of tau species. Whereas HSPB1 only binds tau monomers, DNAJB1 and DNAJA2 recognize aggregation-prone conformers and even mature fibers. In addition, we find that both Hsp40s bind tau seeds and fibers via their C-terminal domain II (CTDII), with DNAJA2 being further capable of recognizing tau monomers by a second, distinct site in CTDI. These results lay out the mechanisms by which the diverse members of the Hsp40 family counteract the formation and propagation of toxic tau aggregates and highlight the fact that chaperones from different families/classes play distinct, yet complementary roles in preventing pathological protein aggregation.
Highlights
Tau is an intrinsically disordered protein (IDP) that is highly expressed in neurons and plays essential roles in microtubule self-assembly and stability (Mandelkow and Mandelkow, 2012), axonal transport (Gustke et al, 1994), and neurite outgrowth (Biernat and Mandelkow, 1999)
We first investigated the effect of DNAJA2 and DNAJB1 on the fibril formation of full-length tau (2N4R) and compared it to that of HSPB1, a well-characterized suppressor of tau aggregation
Addition of DNAJA2 and DNAJB1 chaperones completely inhibited the formation of tau fibrils for over 16 hr (Figure 1B), with no observable ThT signal being detected over this length of time
Summary
Tau is an intrinsically disordered protein (IDP) that is highly expressed in neurons and plays essential roles in microtubule self-assembly and stability (Mandelkow and Mandelkow, 2012), axonal transport (Gustke et al, 1994), and neurite outgrowth (Biernat and Mandelkow, 1999). When tau dissociates from microtubules, it can form oligomers with the potential to disrupt cellular membranes, thereby impairing synaptic and mitochondrial functions, before forming amyloid fibers (Shafiei et al, 2017) These abnormal forms of tau are thought to play a key role in the pathogenesis of various human tauopathies, including Alzheimer’s disease (AD), frontotemporal dementias, and progressive supranuclear palsy (Ballatore et al, 2007). In such cases, tau forms large intracellular aggregates, termed neurofibrillary tangles, whose abundance and localization in the brain correlates with cognitive decline (Ballatore et al, 2007; Brunello et al, 2020). If the fibrils themselves are the neurotoxic species or whether prefibrillar soluble aggregates and oligomers of tau promote neuronal death by spreading tau pathogenicity from cell to cell in a prion-like manner
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