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 (PrPC) is a glycosyl-phosphatidyl-inositol (GPI) anchored glycoprotein that is able to misfold to a pathogenic isoform PrPSc, 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
Highlights
Prion diseases are incurable neurological disorders that produce a broad range of symptoms in mammalian species including humans (Creutzfeldt–Jacob Disease (CJD), Gerstmann–Sträussler–Scheinker (GSS), Fatal Familial Insomnia (FFI), Kuru) and cattle (Bovine Spongiform Encephalopathy (BSE)).Prion diseases are characterized by the misfolding of a normal protein into the pathological β-sheet-rich isoform defined scrapie prion protein (PrPSc), which represents an essential component in the pathophysiology of neurodegenerative prion diseases whose etiology can be infectious, sporadic or genetic.In the case of infectious prion diseases, the formation of nascent prions has been proposed to be driven by a direct interaction between the pathogenic PrPSc template and the endogenous PrPC substrate [1]
We discovered that the intrinsically disordered proteins (IDPs) Shadoo was partially localized in the ER, where it interacted with the ER chaperone Calreticulin, exhibiting a strong tendency to misfold in neuronal cells, and, contrary to canonical secretory proteins, it followed a dual targeting to ER or mitochondria regulated by the mitochondrial chaperone TRAP1 at the interface between ER/mitochondria [22]
Besides the already known indirect interaction mediated by heparan sulfate proteoglycans (HSPGs) between PrPC and non-integrin laminin receptor 37/67 kDa LR [95,96], we have recently found that PrPC is able to directly bind 37/67 kDa LR in neuronal cells, and that a small organic naphtol-derived compound possesses the ability to control both their binding and their trafficking in neuronal cells, representing a new small molecule to be tested, at least against prion disease [97]
Summary
Prion diseases are incurable neurological disorders that produce a broad range of symptoms in mammalian species including humans (Creutzfeldt–Jacob Disease (CJD), Gerstmann–Sträussler–Scheinker (GSS), Fatal Familial Insomnia (FFI), Kuru) and cattle (Bovine Spongiform Encephalopathy (BSE)). The GPI-anchor remodelling steps through the passage to the ER and Golgi (critical cellular organelles for chaperoning folding processes) are essential for the final protein localization in the lipid rafts at the outer leaflet of the plasma membrane, which in turn together with endosomal recycling compartment, has been considered to participate in PrPSc conversion [9]. It has recently emerged the concept of propagating misfolding by which the normal protein, PrPC, becomes misfolded and gain-of-function mechanisms associated with this misfolding propagate further PrPC misfolding in neighboring cells, but can infect other organisms. We highlight the importance of misfolded/pathogenic assemblies’ interaction with membrane components and their roles in the pathogenesis of both prion and Alzheimer’s diseases
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