Attempt to Untangle the Prion-Like Misfolding Mechanism for Neurodegenerative Diseases

Abstract

The misfolding and aggregation of proteins is the neuropathological hallmark for numerous diseases including Alzheimer's disease, Parkinson's disease, and prion diseases. It is believed that misfolded and abnormal β-sheets forms of wild-type proteins are the vectors of these diseases by acting as seeds for the aggregation of endogenous proteins. Cellular prion protein (PrP^C) is a glycosyl-phosphatidyl-inositol (GPI) anchored glycoprotein that is able to misfold to a pathogenic isoform PrP^Sc, the causative agent of prion diseases which present as sporadic, dominantly inherited and transmissible infectious disorders. Increasing evidence highlights the importance of prion-like seeding as a mechanism for pathological spread in Alzheimer's disease and Tauopathy, as well as other neurodegenerative disorders. Here, we report the latest findings on the mechanisms controlling protein folding, focusing on the ER (Endoplasmic Reticulum) quality control of GPI-anchored proteins and describe the "prion-like" properties of amyloid-β and tau assemblies. Furthermore, we highlight the importance of pathogenic assemblies interaction with protein and lipid membrane components and their implications in both prion and Alzheimer's diseases.

Keywords: APP; Aβ; PrP; aggregation; amyloid; misfolding; prion protein; prion-like; seeds; tau.

Figure 1

The ERAD and RESET pathway for degradation of misfolded proteins. (A) Misfolded proteins accumulated in the ER are retrotranslocated from the ER to the cytosol through the translocon (yellow). They are then polyubiquitinated and degraded by the proteasome system. HRD1 (an E3 ubiquitin-ligase) is localized into the ER membrane and mediates the transfer of ubiquitin from ubiquitin-conjugated enzyme E2 to substrates; (B) the ER-stress induced pathway called RESET regulates the degradation of misfolded GPI-anchored proteins, which dissociate from the resident ER chaperones (not illustrated) leaving the ER and reaching the cell surface transiently before lysosomal degradation.

Figure 2

Prion-like mechanism of misfolded protein aggregation. Misfolding of normal physiological form of a protein and formation of pathological seeds is a rare and energetically unfavourable event, based upon exposition of amide groups and high concentration of a given protein. Genetic mutations or environmental factors (e.g., exposure to infective PrPSc, pesticides) can induce the conversion from soluble normal form to insoluble pathological oligomers and larger species that aggregate and fibrillize. Once a seed has formed, thanks to a template-assisted misfolding, each single molecule can acquire a different shape and add to growing aggregates. These latter can be fragmented generating new seeds that are able to accelerate the aggregation, giving life to fibrils formation. Question marks (??) indicate open issues.

Figure 3

Intrinsically disordered proteins and ER import. The ER signal peptides (black rectangle) of the prion protein-like protein Shadoo and APP can mediate alternative targeting to mitochondria. Structural elements (e.g., α-helical domain, GPI-attachment signal) within the nascent polypeptide chain can determine the targeting direction (towards the ER or mitochondria) of these signal peptides. The ER import of nascent chains is efficiently promoted by each signal peptide if the peptide contains α-helical domains, while it targets unstructured polypeptides (IDD, intrinsically disordered domain) to mitochondria. Arrows indicate the direction of protein traffic across the ER.

Figure 4

The molecular chaperone TRAP1 controls the dual ER/mitochondrial targeting of Shadoo. Shadoo is a secretory GPI-AP which is partially localized in the ER. In neuronal cells, Shadoo exhibits a strong tendency to misfold and contrary to canonical secretory proteins, it follows a dual targeting to ER or mitochondria regulated by the mitochondrial chaperone TRAP1 at the interface between ER/mitochondria. The folding properties of Shadoo are partially dependent on association to lipid rafts, whose alteration, as well as proteasomal block, induces its misfolding. Black rectangle: signal peptide; red “zig-zag” line: GPI-anchor. Arrows point to directionality of protein trafficking.