Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases

Abstract

Aberrant accumulation of misfolded proteins into amyloid deposits is a hallmark in many age-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Pathological inclusions and the associated toxicity appear to spread through the nervous system in a characteristic pattern during the disease. This has been attributed to a prion-like behavior of amyloid-type aggregates, which involves self-replication of the pathological conformation, intercellular transfer, and the subsequent seeding of native forms of the same protein in the neighboring cell. Molecular chaperones play a major role in maintaining cellular proteostasis by assisting the (re)-folding of cellular proteins to ensure their function or by promoting the degradation of terminally misfolded proteins to prevent damage. With increasing age, however, the capacity of this proteostasis network tends to decrease, which enables the manifestation of neurodegenerative diseases. Recently, there has been a plethora of studies investigating how and when chaperones interact with disease-related proteins, which have advanced our understanding of the role of chaperones in protein misfolding diseases. This review article focuses on the steps of prion-like propagation from initial misfolding and self-templated replication to intercellular spreading and discusses the influence that chaperones have on these various steps, highlighting both the positive and adverse consequences chaperone action can have. Understanding how chaperones alleviate and aggravate disease progression is vital for the development of therapeutic strategies to combat these debilitating diseases.

Keywords: disaggregation; molecular chaperones and Hsps; neurodegenarative diseases; prion-like spreading; proteostasis.

Figure 1

Amyloid formation and propagation at the molecular level. Native proteins oligomerize after adopting an abnormal β-sheet-rich fold, eventually forming a propagon. Propagons are specific units that can recruit and incorporate native monomers, which allows them to grow into amyloid fibrils. Fragmentation events can lead to complete depolymerization into monomers or to the formation of new propagons that in turn provide more ends for recruiting monomers.

Figure 2

Spreading routes of amyloidogenic proteins. The intercellular transmission of disease proteins can occur via several pathways. Some substrates can be translocated directly across the plasma membrane or shed via microvesicles. Misfolded proteins can be also targeted by all branches of autophagy, and thereby enter the endo-lysosomal system. Aggregates can either be engulfed via bulk or selective (involving adaptor proteins, such as sequestosome 1 (SQSTM1/p62) macroautophagy or taken up into LEs and MVBs through microautophagy. Abnormal proteins may also be directly ingested by lysosomes as a result of CMA. Degradation-resistant aggregates may be released into the extracellular space by lysosomal fusion with the plasma membrane or transported into neighboring cells via TNTs. Endocytosis mediates the uptake of either free protein or extracellular vesicles containing the disease-associated protein. To be released into the cytosol of the receiving cell, misfolded proteins can induce endocytic vesicle rupture. Released proteins can then recruit monomers and catalyze their incorporation, which eventually leads to the formation of amyloid aggregates in the receiving cell. CMA, chaperone-mediated autophagy; LE, late endosome; MVB, multivesicular body; TNT, tunneling nanotube.

Figure 3

Chaperones maintain SG dynamics. Proteins containing intrinsically disordered domains can undergo phase separation upon cellular stress, such as heat stress, and form liquid-like SGs. Under healthy conditions, the SGs are dissolved when the stress subsides. Chaperones (green hexamer) such as Hsp70s, sHsps, and DNAJB6 are involved in the resolubilization process and thus regulate SG homeostasis. Disease-associated mutations in SG associated proteins, the accumulation of DRiPs, or prolonged exposure to stress conditions reduce the fluidity of SGs, leading to a more solid-like structure that promotes amyloid formation over time. The HSPA1A-BAG3-HSPB8 chaperone network (orange hexamer) targets aberrant SGs for degradation. SG, stress granule.

Figure 4

Chaperone interactions during prion-like propagation of disease proteins. The folding and refolding activity of chaperones helps destabilized or misfolded protein species to resume their native state. These transient interactions with misfolded proteins or small oligomers prevent the formation of a seeding-competent propagon (green hexamer). In contrast, the Hsp70 disaggregation machinery can fragment large fibrils leading to the formation of smaller seeding- and spreading-competent species (red hexamer). Chaperones also recognize and sort terminally misfolded forms (orange hexamer) and either mediate their sequestration into an inert deposit (purple hexamer) or deliver them to degradation pathways. Sequestration may reduce the accessibility of fibril ends and thus prevent the further incorporation of native proteins into the amyloid fibril. Extracellular chaperones can also sequester amyloidogenic proteins into large deposits making uptake into receiving cells more difficult. The delivery of amyloidogenic proteins to macroautophagic isolation membranes for their selective clearance is mediated by HSC70 and an sHsp, HSPB8, together with the NEF BAG3 (Gamerdinger et al., 2009). In microautophagy, constitutively expressed HSC70 targets substrates to LEs/MVBs (Sahu et al., 2011). In CMA, HSC70 translocates clients directly across the lysosomal membrane (Tekirdag and Maria Cuervo, 2018). Lysosomes and MVBs can fuse with the plasma membrane releasing either free proteins or exosomes to the extracellular space. In the receiving cell, HSC70 and DNAJC6 are involved in the internalization of misfolded proteins via clathrin-mediated endocytosis by uncoating clathrin-coated vesicles (light blue hexamer; Sousa and Lafer, 2015). By rupturing the endosomal membrane, disease-associated proteins are released from the endocytic vesicle into the cytosol (Flavin et al., 2017), which might be prevented by lysosomal or cytosolic Hsps (yellow hexamer). In the cytosol of the receiving cell, chaperones can finally interfere with the seeding of naïve species by the released propagon (dark blue hexamer). CMA, chaperone-mediated autophagy; LE, late endosome; MVB, multivesicular body; NEF, nucleotide exchange factor; UPS, ubiquitin-proteasome system.