Chaperoning shape-shifting tau in disease

Abstract

Many neurodegenerative diseases, including Alzheimer's, originate from the conversion of proteins into pathogenic conformations. The microtubule-associated protein tau converts into β-sheet-rich amyloid conformations, which underlie pathology in over 25 related tauopathies. Structural studies of tau amyloid fibrils isolated from human tauopathy tissues have revealed that tau adopts diverse structural polymorphs, each linked to a different disease. Molecular chaperones play central roles in regulating tau function and amyloid assembly in disease. New data supports the model that chaperones selectively recognize different conformations of tau to limit the accumulation of proteotoxic species. The challenge now is to understand how chaperones influence disease processes across different tauopathies, which will help guide the development of novel conformationspecific diagnostic and therapeutic strategies. Molecular chaperone function in tauopathiesA class of more than 25 different neurodegenerative diseases, collectively called tauopathies, are associated with brain deposition of fibrillar aggregates of the protein microtubule-associated protein tau (MAPT) [1]. New research in the field has shown that monomeric tau can be converted from a soluble state into a pathogenic state that self-propagates the distinct β-sheet aggregates observed in diseases in a prion (see Glossary) -like manner [2][3][4][5][6][7]. These different states that are observed in vivo are stable, unique conformations that 'seed' or induce the native, inert monomer to assemble into amyloid fibrils or their intermediates [8][9][10][11]. New work on the structures of tau fibrils derived from patient samples have indicated that each tau strain (and/or resulting tauopathy) can be classified by a unique structural polymorph [12,13], implying that there is a direct link between disease and tau conformation. Molecular chaperones bind to tau and modify its conformation to prevent tau assembly and also to disaggregate fibrils. This review will discuss new concepts in tau fibril conformation and the role of molecular chaperones to influence tau strains and their capacity to regulate formation of pathogenic species in disease. We first describe tau function and its aggregation mechanism followed by interactions with molecular chaperones in a hierarchy determined by tau binding, refolding, and disaggregation: J-domain proteins (JDPs), heat shock protein 70 (Hsp70), heat shock protein 90 (Hsp90), and small heat shock protein (sHSP). Importantly, insights into chaperone function in the initial formation and subsequent propagation of distinct tau conformations could guide the design of diagnostic and therapeutic strategies. The MAPTThe human MAPT gene encodes 16 exons, of which exons 2, 3, and 10 are alternatively spliced. In the human brain, tau exists as six isoforms that are defined by the presence or absence of the two N terminal domains (NTDs) and four repeat domains (RDs) (i.e., 2N4R; two NTDs and four RDs; detailed in Figure 1) and are highly expressed in n...

The chaperone Clusterin in neurodegeneration−friend or foe?

“…[ 95 ] In healthy cells, quality control machineries including chaperones HSP40, HSP70, HSP90, and sHSPs normally function in preventing Tau aggregation, but these mechanisms apparently fail in disease. [ 96 ]…”

“…In contrast, Clusterin neutralizes α-Synuclein seeds and therefore, α-Synuclein-Clusterin complexes are unable to template aggregation of endogenous α-Synuclein [14] cells, quality control machineries including chaperones HSP40, HSP70, HSP90, and sHSPs normally function in preventing Tau aggregation, but these mechanisms apparently fail in disease. [96] Clusterin has been shown to interfere with Tau aggregation in vitro by extending the lag phase of fibril formation and slowing fibril elongation. [14,35,36] However, as Tau aggregation is an intracellular process, it would be unlikely to be affected by secreted Clusterin.…”

Tau amyloid polymorphism is shaped by local structural propensities of its protein sequence

“…5f, yellow box ). This peptide contains the previously predicted VEVKSE 337-342 motif 29 , as well as the LDFKDR 344-349 sequence predicted by CORDAX. Again, this agrees with our thermodynamic profile in which both regions constitute stable segments.…”

From Small Peptides to Large Proteins against Alzheimer’sDisease

“…Under healthy conditions, various chaperons (sHSP Hsp40, Hsp70, and Hsp90) regulate the homeostasis of native Tau [ 198 , 199 , 200 , 201 , 202 , 203 , 204 ]. Tau is an intrinsically disordered protein capable of interacting with multiple partner molecules which could be responsible for the development of pathological forms of Tau [ 205 , 206 ].…”