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Review
.2017 Feb 7:11:48.
doi: 10.3389/fnins.2017.00048. eCollection 2017.

The Emerging Roles of Early Protein Folding Events in the Secretory Pathway in the Development of Neurodegenerative Maladies

Affiliations
Review

The Emerging Roles of Early Protein Folding Events in the Secretory Pathway in the Development of Neurodegenerative Maladies

Tatyana Dubnikov et al. Front Neurosci..

Abstract

Although, protein aggregation and deposition are unifying features of various neurodegenerative disorders, recent studies indicate that different mechanisms can lead to the development of the same malady. Among these, failure in early protein folding and maturation emerge as key mechanistic events that lead to the manifestation of a myriad of illnesses including Alzheimer's disease and prion disorders. Here we delineate the cascade of maturation steps that nascent polypeptides undergo in the secretory pathway to become functional proteins, and the chaperones that supervise and assist this process, focusing on the subgroup of prolinecis/trans isomerases. We also describe the chaperones whose failure was found to be an underlying event that initiates the run-up toward neurodegeneration as well as chaperones whose activity impairs protein homeostasis (proteostasis) and thus, promotes the manifestation of these maladies. Finally, we discuss the roles of aggregate deposition sites in the cellular attempt to maintain proteostasis and point at potential targets for therapeutic interventions.

Keywords: aggregation; aggresome; chaperone; endoplasmic reticulum stress; neurodegeneration.

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Figures

Figure 1
Figure 1
Protein folding within the ER lumen. Newly synthesized polypeptides are co-translationally translocated into the ER through the translocon Sec61p complex. Targeting and insertion of the signal peptide is mediated by signal recognition particle (SRP) and at least in the case of PrP, is assisted by FKBP10 (I). In some cases post translational insertion of secretory proteins occurs in an SRP-independent manner, as in case of the GET-mediated insertion of tail-anchored proteins or by the SND mechanism in other cases (II). As the nascent polypeptide exits the translocon, the signal peptide is cleaved and N-linked glycans are added co-translationally by oligosaccharyltransferase (OST) (III). Transmembrane proteins are inserted into the ER membrane and some proteins get anchored to the membrane through the addition of glycophosphatidylinositol (GPI) lipid tail by the transamidase complex (IV). The highly conserved chaperone BiP binds nascent polypeptides as they are translocated into the ER, and maintains them in a state competent for subsequent folding and oligomerization. (V). The peptide undergoes further processing with the help of additional chaperones and folding enzymes, among them the calnexin/calreticulin lectin chaperones, protein disulfide isomerase (PDI) that oxidizes cysteine residues to induce disulfide-bond formation, and the ER resident cyclophilin B (CypB) that catalyzes cis/trans isomerization on the axis of certain proline residues (VI). Properly folded proteins are shipped for further processing in the Golgi (VII). Terminally misfolded proteins are retro-translocated to the cytosol to be degraded by the proteasomes through the ER-associated protein degradation (ERAD), often mediated by the E3 ubiquitin ligase HRD1 and the ATPase VCP/p97 (VIII). Sometimes, ERAD substrates and excess membranes and membrane proteins are shuttles for degradation in the lysosome via macro-ER-phagy (IX).
Figure 2
Figure 2
Cellular deposition sites. When the burden of misfolded proteins exceeds the cell's clearance and refolding capacity, potentially hazardous aggregates accumulate within the ER. Under certain circumstances, these aggregates are actively convoyed to designated deposition sites. Aggresomes or aggresome like-structures (I) are cytosolic juxta-nuclear inclusion bodies that serve as quality-control centers. Another type of a cytosolic deposition site is the insoluble protein deposit (IPOD) (II) where terminally aggregated proteins tend to accumulate. Intra-nuclear quality control compartment (INQ) (III) resides in the nucleus next to the nucleolus and harbors nuclear as well as cytosolic misfolded proteins. Some proteins that aggregate within the ER are deposited in the ER-derived quality-control compartment (ERQC) (IV).
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