The intricate mechanisms of neurodegeneration in prion diseases

Abstract

Prion diseases are a group of infectious neurodegenerative diseases with an entirely novel mechanism of transmission, involving a protein-only infectious agent that propagates the disease by transmitting protein conformational changes. The disease results from extensive and progressive brain degeneration. The molecular mechanisms involved in neurodegeneration are not entirely known but involve multiple processes operating simultaneously and synergistically in the brain, including spongiform degeneration, synaptic alterations, brain inflammation, neuronal death and the accumulation of protein aggregates. Here, we review the pathways implicated in prion-induced brain damage and put the pieces together into a possible model of neurodegeneration in prion disorders. A more comprehensive understanding of the molecular basis of brain degeneration is essential to develop a much needed therapy for these devastating diseases.

Figure 1. Multiple neurodegenerative pathways are implicated in TSEs

(a) The conversion of the natively folded PrP^C into PrP^Sc triggers disease. The structure of PrP^C corresponds to the experimentally determined tridimensional conformation of the protein by nuclear magnetic resonance [91] and the structure of PrP^Sc corresponds to a model based on low resolution techniques [92]. (b) Abnormalities in the brain of infected individuals include the accumulation of PrP^Sc deposits, synaptic damage and dendrite loss, spongiform degeneration, brain inflammation and neuronal death. PrP^Sc deposition was determined after immunohistochemical staining with anti-PrP antibodies (black arrow heads). Dendrites were labeled by Golgi-silver staining to illustrate the substantial decrease on dendrites and synaptic connections in prion infected animals; this picture was reproduced from ref [130] with authorization (Copyright National Academy of Sciences, USA). Spongiform degeneration was evaluated after hematoxylin and eosin staining. Astrogliosis (brain inflammation) was detected by immunohistochemical staining of reactive astrocytes with an anti-GFAP (Glial fibrillary acidic protein) antibody. Apoptosis was detected by staining with caspase-3 antibody (red indicated by white arrow heads) and DAPI (4′,6-diamidino-2-phenylindole, blue) staining of nucleus. For each stain, pictures from prion infected (upper) and controls (lower) are shown.

Figure 2. Putative signaling pathways for PrP^Sc-induced neurodegeneration in prion diseases

Several mechanisms have been proposed by which PrP^C to PrP^Sc conversion results in neurodegeneration. PrP^Sc might produce mitochondrial stress, leading to apoptosis by the well-known pathway involving translocation of the proapoptotic proteins Bax and Bad and the release of cytochrome C, which forms the apoptosome [85]. Formation of this complex activates caspase-9, which in turn activates the executor caspase-3. An alternative model implicates sustained ER stress [93]. Chronic ER stress results in the activation of the ER-resident caspase-12 (caspase-4 in humans), which in turn cleaves and activates caspase-3 [13]. Another proposed mechanism by which ER stress leads to neurodegeneration involves hyperactivation of the phosphatase calcineurin owing to extensive calcium release from the ER. Activated calcineurin dephosphorylates several important proteins, including the transcription factor CREB and the proapoptotic protein Bad, resulting in synaptic damage and neuronal death. Several or all of these pathways and perhaps others (such as autophagy or neuronal death induced by synaptic and dendritic loss) could be operating simultaneously in the brain of prion-infected individuals, which would explain why knocking out one specific signaling pathway does not substantially change the progression of the disease.

Figure 3. Schematic model of neurodegeneration in prion diseases

The disease process starts with the formation of PrP^Sc, beginning a long and clinically silent presymptomatic phase, in which PrP^Sc slowly but gradually accumulates in the brain. PrP^Sc accumulation triggers ER stress and activation of the UPR, which represents the first line of defense against protein misfolding. Other early consequences of PrP^Sc accumulation are brain inflammation (in the form of astrocytosis and microglial activation) and autophagy. Both inflammation and autophagy might initially be defensive mechanisms, but later could also contribute to neuronal death and perhaps brain vacuolation. The first damage leading to noticeable clinical consequences is likely synaptic disruption, ending the presymtomatic phase and beginning the early clinical phase of the disease. Synaptic dysfunction produces loss of dendrites and finally neuronal death. The end and irreversible stages of the disease are characterized by massive spongiform degeneration and neuronal death, which likely are triggered by a variety of interconnecting cellular pathways.