Garth F Hall*
Department of Biological Sciences, University of Massachusetts Lowell, 198 Riverside Street Lowell MA, USA
Received date: November 26, 2012; Accepted date: November 28, 2012; Published date: December 10, 2012
Citation: Hall GF (2012) Is it Premature to assume that Prion-like Propagation of Protein Misfolding is the Universal Model of Lesion Spread in Neurodegeneration?. J Alzheimers Dis Parkinsonism 2:e124. doi:10.4172/2161-0460.1000e124
Copyright: © 2012 Hall GF. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Neuron death; Interneuronal lesion spread; Tau secretion; Prion; Templated misfolding
PrP: Prion protein; ASN: Alpha synuclein; AD: Alzheimer’s disease; APP: Amyloid precursor protein
New information about the secretion, uptake and toxicity of key proteins associated with human neurodegenerative disease has led to rapidly changing assumptions about the nature of interneuronal mechanisms of pathogenesis and a sharp focus on protein templating mechanisms. While the evidence for “prion-like” roles for non-PrP proteins such as tau and alpha synuclein in mechanisms of lesion spreading is becoming more persuasive, we believe that the exclusive focus on such mechanisms as a common mechanism of lesion spreading is premature and may be counterproductive to a full and subtle understanding of human neurodegenerative disease mechanisms.
One of the most exciting themes emerging from recent neurodegenerative disease research has been the idea that the toxic effects of abnormal protein aggregation can spread between neurons in the CNS. This idea has been attractive ever since the publication of the “Braak sequence” of neurofibrillary lesion progression in Alzheimer’s disease (AD) , and has long been supported by correlative studies of AD [2,3], non AD tauopathies [4,5] and Lewy Body disease  as a general neurodegenerative disease mechanism. More recently, direct cellular-level evidence for lesion spreading via the interneuronal transfer of disease-associated aggregation-prone proteins (e.g. PrP, beta amyloid, alpha synuclein, tau) has been provided by demonstrations that even cytosolic members of this group such as tau are actively secreted and taken up into adjacent and transsynaptic neurons [7-10]. In all of these proteins, this apparently occurs via disease-modulated mechanisms known to affect conformation state [7,8,10-16] and is often synergistic, neatly accounting for extensive overlaps seen between neurodegenerative syndromes [17-21]. Most interestingly, these proteins can be secreted via a common unconventional mechanism [11,22-24] involving exosomes, suggesting that all of the major human neurodegenerative diseases might share a common pathogenesis [25-29]. These findings, together with the vindication of the “prion hypothesis” as the central mechanism of transmissible spongiform encephalopathies such as Creutzfeld-Jacob Disease [30,31] and the propagation of multiple disease-specific conformations of PrP via “templated misfolding” [32,33] have lent strong support to the possibility that a “prion-like” mechanism (i.e. templated misfolding of normal proteins into disease-specific conformations via direct interactions with the same protein in a disease-specific conformation) may be applicable to ASN, Abeta and tau as well as the prion protein itself. If so, this would mark a major increase of our insight into neurodegeneration mechanisms, with potentially revolutionary implications for the clinical diagnosis and treatment of neurodegenerative disease.
An unfortunate consequence of the (mostly quite justified) excitement about the evidence for prion-like propagation of non PrP disease-associated proteins is the tacit but apparently widely held assumption that the prion-like propagation of misfolded conformations excludes all other possible mechanisms of lesion spreading. An exclusive focus on such mechanisms has become prominent in recent reviews of this topic, at least with respect to tau protein [26,27,34,35] and is particularly notable in studies based on results from transgenic animal disease models in which intercellular tau transfer in situ can only be assessed indirectly [36,37]. This tendency is surprising given the extremely high evidentiary threshold that the original prion hypothesis had to face, the very recent nature of the data directly supporting prion-like mechanisms and our still quite fragmentary understanding of interneuronal protein transfer at the cellular level of analysis in the CNS. It is unfortunate because it threatens to close investigator’s minds to additional or alternate mechanisms before enough is known about the subject at the cellular level to make a considered judgment.
Interneuronal transfer of non-PrP “disease” proteins has already been extensively demonstrated in disease models and when combined with the persuasive correlative neuropathological evidence described above makes a powerful case that direct interneuronal mechanisms of lesion spreading play a central role in human neurodegeneration. A fairly strong case can also be made for the involvement of prion-like mechanisms in the interneuronal transfer of neurotoxicity that involves non-PrP proteins in at least some circumstances. Common features of PrP and non-PrP disease proteins consistent with such a role include 1) a demonstrated toxicity mechanism linked to oligomerization , 2) an involvement with plasticity/memory associated synaptic functions [39,40] some of which may require long term conformational changes in specific proteins that appear to correlate with prion-like behavior [41-43], and 3) physical properties such as having multiple stable conformations and a chaperone-like ability to interact with other proteins and influence their conformations . Recent cellular studies that suggest that templating might actually mediate toxicity or at least aggregate propagation [45,46]. While such studies certainly strengthen the case for the involvement of conformationally mediated propagation of abnormally folded proteins in at least some circumstances, they have little to say about the viability of other possible explanations.
This can be summarized by saying that we simply do not know nearly enough about interneuronal aspects of neurodegeneration to focus exclusively on one possible transmission mechanism, however attractive it might be. The one protein (PrP) for which the prion mechanism has been established has an extraordinary subtlety of form, permitting multiple conformations that lead to multiple distinct diseases [32,33,47]. However, this occurs without the requirement for consensus sequences, suggesting that we still have a great deal to learn about the actual molecular mechanism involved . This, combined with our relatively poor understanding of the secretion/uptake and toxicity mechanisms operative in TSEs make the extension of templated misfolding mechanisms to other diseases/proteins while excluding consideration of other mechanisms seem premature. Also, aggregationprone proteins in neurodegenerative disease have common properties that may mediate lesion spread and neurotoxicity (e.g. via inducing endosome-lysosome abnormalities) without the need to invoke prionlike mechanisms . Such proteins also share many physical properties and developmental functions in common with tissue morphogens (e.g. exosomal secretion, susceptibility to lipidation, roles in axonogenesis and guidance, HSPG binding) . Tau particularly resembles Wnt morphogens in that it is efficiently secreted via exosomes, interacts with signal transduction pathways that regulate axonal guidance and neuronal polarization, but also modulates cell cycle re-entry and apoptosis [51-53]. Most interestingly, tau and multiple elements of the Wnt pathway are both co-enriched in secreted exosomes  and disregulated in AD ; raising the possibility that reactivation of tissue patterning genes could be a potential model for lesion propagation and toxicity. Of course, such a speculative pathway cannot now be considered a serious alternative to “prion-like” templating in neurodegenerative disease. However, the existence of this and many other unexplored intercellular aspects of these diseases suggests that we do not yet understand the biology of tau APP/Abeta ASN etc. nearly well enough to abandon consideration of “non-prion” alternatives as lesion spreading mechanisms. Indeed, the existence of an alternative pathway of transfer and toxicity has already been demonstrated for tau protein, in which N terminal fragments of tau can both be transferred between neurons  and mediate toxicity without the presence of its microtubule-binding domain [55-58], which is required for oligomer (and thus presumably for prion) formation. Interneuronal toxicity transfer in this pathway is apparently largely via receptor mediated mechanisms [55,59], a mechanism that is (at least on its face) hard to reconcile with conformational templating. However, the Ca++ fluxes associated with N terminal tau toxicity might conceivably mediate neurofibrillary lesion propagation by inducing cleavage-mediated aggregation of endogenous tau in recipient cells via calpain and caspase activation, a mechanism that (ironically) would technically satisfy the original Prion Hypothesis without involving templated Misfolding .
In our view, the best argument against adopting the “prion assumption” in the case of non-PrP neurodegenerative diseases is historical-we have after all been here before. The history of neurodegenerative disease research is replete with instances where major findings led rapidly to the wide adoption of far-reaching, plausible and largely correct assumptions that nevertheless now appear to have been counterproductive to overall progress in the field due to their suppressive effect on research into alternatives. The clearest (but by no means the only) example of this was the widespread abandonment of non-Abeta related lines of inquiry following the identification of FAD mutations in APP and the ensuing assumption by many that other contributors to AD etiology (e.g. tau misprocessing in endosomes, cell cycle re-entry etc.) must therefore not be that important. The underlying culprit here was not the (correct) assumption of the central importance of APP misprocessing in AD. Rather, the problem lay with the tacit corollary that AD is simple; that since APP misprocessing to Abeta is centrally important, other critical factors that must be understood before effective diagnostics and treatments for AD can be devised did not exist. This was clearly mistaken in retrospect and very likely set back our understanding of AD cytopathogenesis significantly.
The moral to be drawn from our experiences over the past 20 years thus seems clear. We have repeatedly been shown how complicated and subtle neurodegenerative disease mechanisms are and thus how important resisting assumptions that give rise to an unduly simplified view of them can be.
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