The conformational diseases, linked to protein aggregation into amyloid conformations, ranked from neurodegenerative affections such as Alzheimer, Parkinson (PD), Huntington (HD), Frontotemporal dementia (FD), amyotrophic lateral sclerosis (ALS) or human transmissible sporadic encephalopathies (TSEs) commonly known as prion diseases, to non-neurodegenerative systemic and localized amyloidosis as senile systemic amyloidosis or type II diabetes, respectively.1 Nowadays 36 million people worldwide have some form of dementia, predicted to exceed 65 million by 2030 and become tripled by 2050. Nevertheless, whereas Alzheimer disease represents ï¾70% of these cases, sporadic Creutzfeldt-Jakob disease (CJD), representing about 85% of all human TSEs, has a worldwide death rate of about 1 case per million people each year.
Although amyloids are considered as universal and omnipresent structures sharing enclosed patterns,1 prions represent only a fraction of a drop in the amyloid ocean in which the aggregation process becomes self-perpetuating and infectious, pathological in mammals and protein-based genetic elements in fungus.2 Nevertheless, an essential question has been for a long time raised: "Could even AD and other conformational diseases become infectious?". Interestingly, although it has long known that AD and other dementias were the result of a widespread gradually mounting defect in neuron biochemistry, recent works suggest that amyloid-like proteins linked to these diseases could spread from cell to cell as a network in the brain; so as cell-to-cell infection.3 However, these processes are far from the neuronal invasion produced in prion diseases wherein prion infectivity transfers from the spleen to the central nervous system (CNS) in a biphasic model with the first phase characterized by widespread colonization of lymphoreticular organs and the second one involving peripheral nerves, probably acting in concomitance with vesicle-associated infectivity, and cell-free, free-floating oligomeric or protofibrils infectious particles.2 So the essential unresolved question: "Why does an amyloid become infectious?" rests yet.
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Fungal prions, which provide an excellent model for the understanding of amyloid formation and propagation, could enlighten the key factors leading to an amyloid to become a prion. Interestingly, as shown in the yeast prion [PSI+] caused by the amyloid aggregation of Sup35 protein, the amyloid fibril growth and division (fibril fragmentation) rates determine the number of events (named also "propagons") per cell, and so, following the Poisson law, the prion infectivity probability.4 However, an essential difference exists between mammal prion protein (PrP) and yeast prion proteins: the toxicity of theirs protein aggregates. While the amyloid aggregation of PrP (PrPSc) is highly toxic for the neuronal cells, the yeast prions do not entail cellular surveillance problems for the yeast. Importantly, the cytotoxicity is an intrinsic characteristic shared by all protein involved in conformational diseases. So could both the intrinsic cytotoxicity of each amyloid and the number of events per cell be determinant factors in the differentiation between infectious and non-infectious amyloids in humans?
Recent findings in the HET-s/HET-S heterokaryon incompatibility system, a self/non-self recognition phenomenon of the filamentous fungus Podospora anserina might, therefore, shed light on the cytotoxicity effect in the prion persistence. The incompatibility reaction between two genetically distinct strains is triggered when a strain expressing soluble HET-S is seeded by contact with another one expressing HET-s prion. Despite HET-S, sharing homology of 96% with HET-s, forms in-vitro amyloid aggregates extremely similar to those of its partner (R.S. personal communication), its in-vivo amyloid fibrils can be only localized into dead heterokaryon cells because the dramatic toxic effect of these amyloid aggregates.5 This extreme case illustrates as the cytotoxicity can swing between non-transmissible amyloid (HET-S fibrils) and transmissible prion (HET-s fibrils).
As shown in Fig. 1, it could be suggested that amyloid aggregates may surfer between non-infectious (or negligibly infectious) and infectious material, depending on the number of events per cell and the cell surveillance (indicative parameter of the intrinsic cytotoxicity of each amyloid). Importantly, although the number of events per cell is directly related with the replication efficiency, other parameters as resistance to biological clearance, bioavailability, transport and spreading, and transmission of phenotypic changes must be taken into consideration.3 However, since the amyloid species of discrete size as oligomers and not the mature amyloid fibers (1) mediate the main cytotoxic effect in conformational diseases,1 (2) they are considered as a potential source of prion infectivity,2 (3) they are more easily transportable and spreading, and (4) they are directly related to infective nuclei amount, both the number of events per cell and amyloid toxicity could represent an excellent report of the infectivity.
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In dementia, the neuronal death is triggered by the intrinsic cytotoxicity of each amyloid. However, while aggregates are sufficiently toxic, the neuronal damage rate is related to the number of toxic events and cell surveillance (see the dotted area in Fig. 1). Thus, whereas high toxicity could undergo remarkably low infectivity (cell-to-cell transmission) inasmuch as the fast cell death dramatically reduces the number of transmissible events into the cell, less toxicity and so higher cell surveillance could contribute to increased infectivity because significant amounts of transmissible events could be into the cells before its death (neuronal invasion). Since all protein involved in dementia could be considered as neurotoxic elements in their amyloid form, finally undergoing the neuronal death, it would have to be expected that the most transmissible amyloids, as PrPSc, are involved in the most fast and fatal diseases as it happens.
Figure 1. Graphical representation of the effect of events per cell and cell surveillance on amyloid infection capacity. From low transmission (green), to high (red) capacity. The neuronal damage region is represented as accumulated Gaussian distribution (violet dotted region) containing the proteins involved in human neurodegenerative diseases. Amyloid ï¢-peptide (Aï¢) and infectious prion protein (PrPSc) have been added as representative examples of non-prion and prion amyloid proteins.
In the cell, the protein folding and aggregation are on competing pathways controlled by a delicate multi-step equilibrium highly dependent on both intrinsic and extrinsic factors. In the same manner, the amyloid aggregation is a consequence of balance among multitude of conformational states and interconvert between them in a complex network of equilibria.1 So, alterations in the cellular environment (i.e. under conditions of stress or modifications in the transcription and protein expression levels could) become crucial in the election of a particular self-assembly pathway, determining the final amyloid structure and/or structures (as a consequence of polymorphisms).
The fact that all amyloids could be considered prions, from cell-to-cell transmission to real neuronal invasion, entails serious repercussions in medicine. Thus, both cellular environmental changes and intrinsic cell properties of each patient may directly or indirectly induce different self-aggregation pathways, undergoing diverse amyloid structures, different cell resistances to amyloid toxicity and in consequence diversified prion propensities and cytotoxicity rates (see arrows in Fig. 1). On the one hand, it could explain because severe symptomatology (i.e. in Alzheimer disease) can be associated to low neuronal damage and vice versa. On the other hand, this could also elucidate because the severity and progression of each dementia depends of each patient and disease. In addition, important repercussions in dementia therapies would take in consideration because amyloid toxicity reduction, cell protection or amyloid plaques disruption treatments could produce opposite effects to those expected.