Proteostasis unbalance in prion diseases: Mechanisms of neurodegeneration and therapeutic targets

Abstract

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are progressive neurodegenerative disorders of the central nervous system that affect humans and animals as sporadic, inherited, and infectious forms. Similarly to Alzheimer's disease and other neurodegenerative disorders, any attempt to reduce TSEs' lethality or increase the life expectancy of affected individuals has been unsuccessful. Typically, the onset of symptoms anticipates the fatal outcome of less than 1 year, although it is believed to be the consequence of a decades-long process of neuronal death. The duration of the symptoms-free period represents by itself a major obstacle to carry out effective neuroprotective therapies. Prions, the infectious entities of TSEs, are composed of a protease-resistant protein named prion protein scrapie (PrP^Sc) from the prototypical TSE form that afflicts ovines. PrP^Sc misfolding from its physiological counterpart, cellular prion protein (PrP^C), is the unifying pathogenic trait of all TSEs. PrP^Sc is resistant to intracellular turnover and undergoes amyloid-like fibrillation passing through the formation of soluble dimers and oligomers, which are likely the effective neurotoxic entities. The failure of PrP^Sc removal is a key pathogenic event that defines TSEs as proteopathies, likewise other neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease, characterized by alteration of proteostasis. Under physiological conditions, protein quality control, led by the ubiquitin-proteasome system, and macroautophagy clears cytoplasm from improperly folded, redundant, or aggregation-prone proteins. There is evidence that both of these crucial homeostatic pathways are impaired during the development of TSEs, although it is still unclear whether proteostasis alteration facilitates prion protein misfolding or, rather, PrP^Sc protease resistance hampers cytoplasmic protein quality control. This review is aimed to critically analyze the most recent advancements in the cause-effect correlation between PrP^C misfolding and proteostasis alterations and to discuss the possibility that pharmacological restoring of ubiquitin-proteasomal competence and stimulation of autophagy could reduce the intracellular burden of PrP^Sc and ameliorate the severity of prion-associated neurodegeneration.

Keywords: autophagy; neurodegeneration; prion protein; proteasome; protein misfolding.

Figure 1

Schematic representation of the interplay between exosome release and autophagy to reduce the intracellular burden of PrP^Sc. PrP^C (green) conversion into neurotoxic PrP^Sc isoform (red) occurs during PrP^C recycling through a stochastic event or after interaction with exogenous PrP^Sc. Neuronal strategies to remove cytoplasmic PrP^Sc comprehend protein degradation through macroautophagy or PrP^Sc insertion into exosomes contained in multivesicular bodies (MVBs). MVBs can either release exosomes containing PrP^Sc, or reenter the autophagy cycle through the formation of autophagosomes, amphysomes (not depicted in the figure) and autolysosomes.

Figure 2

Schematic representation of protein quality control mechanisms of misfolded PrP. Structural aberrancy of nascent PrP^C (spontaneously occurring or favored by PRNP mutations) is sensed in the ER leading to the recruitment of chaperones that block PrP^C in unfolded state until proper folding (1) is restored. Terminally misfolded PrP is translocated in the cytosol (2) for lysosomal chaperone associate autophagy (CMA) (3) or ubiquitination (red dots: ubiquitin moieties) (4) and proteasomal digestion (5). Cytosolic aggregates of ubiquitinylated PrP escape proteasome (6) and are clustered in larger inclusion bodies by the intervention of adaptor proteins mainly p62 (7). P62 drives the aggregates toward the nascent phagophores that engulf PrP clusters in autophagosomes (8). Autophagosomes fusion with lysosomes produces digestion of aggregates (9) and recycling of nutrients (10).