Abstract
In several neurodegenerative diseases, such as Parkinson, Alzheimer’s, Huntington, and prion diseases, the deposition of aggregated misfolded proteins is believed to be responsible for the neurotoxicity that characterizes these diseases. Prion protein (PrP), the protein responsible of prion diseases, has been deeply studied for the peculiar feature of its misfolded oligomers that are able to propagate within affected brains, inducing the conversion of the natively folded PrP into the pathological conformation. In this review, we summarize the available experimental evidence concerning the relationship between aggregation status of misfolded PrP and neuronal death in the course of prion diseases. In particular, we describe the main findings resulting from the use of different synthetic (mainly PrP106-126) and recombinant PrP-derived peptides, as far as mechanisms of aggregation and amyloid formation, and how these different spatial conformations can affect neuronal death. In particular, most data support the involvement of non-fibrillar oligomers rather than actual amyloid fibers as the determinant of neuronal death.
Highlights
Most proteins evolved to efficiently fold into a unique native structure, misfolding occurs frequently in vivo [1]
We demonstrated that G114 and G119 are the main determinants for the fibrillogenesis of PrP106-126
From a biological point of view, PrP106-126AA showed similar biological effects to the wt peptide, being able to induce apoptotic cell death through the activation of the p38 MAP kinase cascade [48]. These data indicate that glycines 114 and 119 in PrP106-126 sequence are major determinants required for the fibrillogenesis of the peptide, likely due to the high flexibility that they introduce in the molecular structure, but are not required for the activation of the apoptotic pathway [48]
Summary
Most proteins evolved to efficiently fold into a unique native structure, misfolding occurs frequently in vivo [1]. It was proposed that intracellular and/or extracellular protein aggregates in most neurodegenerative diseases can cross cellular membranes and directly contribute to the production of novel misfolded units and the propagation of neurodegeneration in a prion-like model [4]. Two main mechanisms have been proposed to explain the auto-propagation of PrPSc from newly synthesized PrPC and the final aggregation in amyloid fibrils: nucleation-polymerization (A) and template assisted (B) models. Treatment with luminescent conjugated polymers (LCPs) renders PrPSc, but not PrPC, more resistant to proteinase K (PK) proteolysis, but profoundly reduces prion infectivity through the induction of hyperstabilization, rather than destabilization, of PrPSc deposits [26] These findings suggest that hyperstabilized mature fibrils are not correlated to prion infectivity. A dissociation between PK resistance and infectivity of prions was highlighted, questioning the use of PK resistance as sole screening parameter to detect infective prions [26]
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