Abstract

Introduction

Prionopathies are unique among neurodegenerative diseases because they are infectious, that is, spontaneous transmission from one individual to another has occurred outside of an experimental setting. Prion diseases derive from protein misfolding, which in rare cases can be due to exposure to exogenous prion species¹ – that is, “infection”– but are usually due to events that occur spontaneously within the individual. The prion protein in its nonpathogenic form (PrP^C) is expressed in many human cell types². When PrP^C comes into contact with a pathogenic prion protein conformer (PrP^Sc), PrP^C is induced to misfold in a process termed “templated conformation change.” Through this interaction, the conformation of a misfolded PrP^Sc molecule is communicated to a native PrP^C protein³. This interaction may involve other proteins within the cell, and it is unknown whether one or more PrP^Sc molecules form the pathogenic “seed.”

Recent studies are now highlighting prion-like mechanisms of propagation of protein misfolding in a variety of common, non-infectious (that is, transmission between individuals has never been shown outside experimental conditions), neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), Parkinson disease (PD), and polyglutamine diseases. Like prionopathies, all of these diseases are associated with the accumulation of fibrillar aggregates of proteins such as tau, amyloid-β (Aβ), α-synuclein, and polyglutamine proteins. With the exception of polyglutamine diseases, which derive from an unusual mutation that produces a protein with an abnormally long glutamine tract, sporadic cases of these diseases involve the wild-type form of each protein, whereas rarer, autosomal dominant forms of the disease are linked to mis-sense or splicing mutations. Similarly, although prion diseases are defined by their infectivity, most prion disease cases actually arise sporadically from wild-type protein, or through inherited mutations in the prion protein⁴. This article will highlight two important commonalities between prion and non-prion neurodegenerative diseases—phenotypic diversity and spreading pathology—and will review basic research that is beginning to elucidate the biochemical and cellular basis of these similarities.

Phenotypic Diversity

Most common neurodegenerative diseases manifest myriad disease phenotypes. In AD, the speed of cognitive decline, age of onset, and the location and extent of Aβ plaque load vary considerably ^5–7. Aβ aggregates are also present in muscle fibers in inclusion body myositis, a common age-related inflammatory muscle disease⁸, and in the vascular wall in cerebral amyloid angiopathy⁹. PD, dementia with Lewy bodies, and multiple system atrophy are all associated with α-synuclein deposition¹⁰, yet are strikingly distinct clinical syndromes. PD is associated with α-synuclein mis-sense mutations^{11, 12}, as well as gene amplification^13–15. Most remarkably, tau aggregation is a pathological hallmark of more than twenty different neurodegenerative diseases, including AD¹⁰ and frontotemporal dementia with Parkinsonism (FTDP-17), a familial form of disease caused by mutations in the tau gene¹⁰. Sporadic tauopathies vary considerably in brain region involvement, disease duration, age of onset, and fibril morphology¹⁰.

Prion diseases also have very diverse phenotypes, involving both the central and peripheral nervous system, exhibit distinct rates of progression^{16, 17}, and can derive from mutations within the prion protein gene¹⁸. The wild-type prion protein (PrP) is the causative agent for Kuru¹⁹ and sporadic Creutzfeldt-Jakob Disease (CJD), among others. Prions also cause fatal familial insomnia^20–22. Thus, variation in presentation and course of disease defines both prion and non-prion based neurodegeneration. Distinct conformations of pathogenic proteins could play a key role in determining the phenotypic diversity of non-infectious neurodegenerative diseases.

Spreading Pathology

Neurodegenerative diseases begin with dysfunction in a discrete region, whereas at later stages they typically involve much larger areas of brain. Pathology often occurs within particular neural networks, and progresses in a predictable manner. For example, the transentorhinal region first shows signs of deterioration and tau pathology in AD. Glutamatergic cells in this region project into the entorhinal cortex, which is the next to degenerate. Lesions of the hippocampus, amygdala, and the neocortex follow³¹. Recent studies of normal and demented patients using functional imaging have corroborated these pathological studies, and have shown that degeneration in distinct neurodegenerative diseases such as AD, corticobasal ganglionic degeneration, and FTD follow patterns of intrinsic neuronal connectivity present in normal individuals³². PD is well known to begin with motor symptoms that are largely caused by the degeneration of dopaminergic neurons within the substantia nigra; however, a substantial fraction of patients go on to develop dementia implying that additional brain regions are involved ³³. Likewise, in amyotrophic lateral sclerosis, the progression of symptoms locally within the spinal cord and the combined degeneration of upper and lower motor neurons is well known³⁴. Taken together, these observations suggest a pathogenic link between one affected cell and its neighbor. Despite these patterns of disease progression, there is not yet clear experimental evidence that this progression of neurodegenerative diseases other than prionopathies results from the ‘spread’ of disease from one area to another.. Prionopathies begin with a tiny inoculum, such as a contaminated surgical device or transplanted tissue, or the spontaneous accumulation of PrP^Sc in a single cell or group of cells. PrP^Sc propagation depends on a network of PrP^C-expressing cells³⁵. Ultimately, however, pathology involves a large area of the nervous system³⁶. This may occur via spread through neuronal networks. In hamsters, orally derived PrP^Sc appears to spread along the vagus nerve to the medulla, pons, midbrain, cerebellum, and thalamus via neuroanatomical pathways³⁷. And two studies have observed that PrP^Sc injected into the eye travels along defined neuroanatomical connections to involve larger brain regions^{38, 39}.

Distinctions between diseases

Crucial distinctions remain between the prionopathies and common neurodegenerative diseases. Most importantly, there is no evidence, despite decades of study, of true, spontaneous “infectivity” for any sporadic disease such as AD, FTD, or PD. The biophysical properties that allow a protein to be eaten, passage through the digestive system, and then be absorbed to replicate in the host before infectious particles make their way to the brain clearly sets prion proteins apart from any other known amyloid protein associated with neurodegenerative disease. However, Serum amyloidosis A (SAA) has been studied as another potentially infectious amyloid disease⁵⁵ derived from misfolding of the serum amyloid A protein⁵⁶. Although this amyloidosis is not associated with neurodegeneration, it has many features of transmission similar to prionopathies, including an oral route⁵⁷.

In addition, most prionopathies exhibit relatively rapid progression within the CNS, with sCJD averaging 4–6 months from symptom onset to death⁵⁸, whereas common neurodegenerative diseases generally progress over many years. Finally, whereas PrP is a transmembrane protein, which could in theory more easily allow trans-cellular propagation, tau and synuclein normally function within the cell, and thus it is more difficult to understand how they could accomplish trans-cellular movement.

A common model of propagation?

Even taking into account these distinctions, increasing experimental evidence is now suggesting that basic cellular mechanisms of trans-cellular prion propagation may be applicable to a wide range of protein pathologies. In this model (Fig. 1), fibrillar protein “seeds” from adjacent or synaptically connected cells may be taken up to induce aggregation of otherwise normally structured protein. The propensity for this to occur could be influenced by splice isoforms and post-translational modifications of the proteins involved. This model could explain both for the phenotypic diversity observed in sporadic neurodegenerative disease, in which a single protein underlies a variety of conditions, and for the inexorable spread of pathology, in which aggregates are capable of moving between cells to propagate misfolding. It also can explain the involvement of neuronal networks in neurodegeneration. If these ideas are fully validated in animal models, they will suggest an important new conceptual framework with which to consider pathogenesis of an enormous range of neurodegenerative diseases.

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Figure 1

Potential mechanisms for trans-cellular propagation of protein misfolding

(A) Intracellular protein aggregation leads to cell death. This results in release of protein aggregates into the extracellular space, which are subsequently taken up and corrupt protein folding in vulnerable cells. (B) As part of the physiology of a living cell, protein aggregates may be released, potentially via exosomes or exocytosis. This results in protein aggregates in the extracellular space that may be taken up by adjacent cells. This mechanism can account for local propagation of misfolding, along with (A). (C) Aggregates might cross synapses. Release could be due to local degeneration of a synapse, normal synaptic physiology, or as part of an exocytic process as in (B). This mechanism can explain network degeneration in neurodegenerative diseases.

Implications for Treatment

If non-infectious neurodegenerative diseases and prionopathies have similar mechanisms of progression, this will have important therapeutic implications. Current therapies for neurodegenerative diseases generally target non-specific mechanisms to prevent cell death and promote neuron survival, or they focus on disease-specific events that govern stability and clearance of target proteins inside and outside of cells. If protein misfolding in one cell can trigger similar events in a neighbor, then new therapeutic strategies based on halting non-cell autonomous effects will be required. For example, stem cell therapies may have limited utility unless it is possible to render the transplanted cells resistant to the effects of misfolded protein from the host. On the other hand, new approaches based on antibody therapies may have much wider application than previously realized, where the main focus as been on extracellular Aβ. Indeed, vaccination of mice in experimental models of tauopathy and synucleinopathy (which involve intracellular proteins) has been reported to ameliorate pathology^{59, 60}. Finally, as mechanisms of aggregate uptake and cell-to-cell transmission are determined, it may be possible to design novel pharmacological interventions that block disease progression (Fig. 2).

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Figure 2

New therapeutic approaches

If trans-cellular propagation of protein misfolding occurs, then new strategies could supplement existing approaches to promote cell survival and block intracellular accumulation of misfolded species. As the cellular mechanisms of aggregate release and uptake are delineated, it may be possible to inhibit these events pharmacologically or genetically. Antibody-based therapies might also be expanded to target protein aggregates that are generated inside a cell and released into the extracellular space.

Conclusions

It is now clear that a variety of disease-associated proteins, not just PrP, exhibit templated conformational change that might underlie certain aspects of phenotypic diversity of disease. Given the clear predictions of this model, future studies should be able to clearly test this idea. The phenomenon of cell-cell transfer of protein aggregates is now well established in cell culture, and mouse models suggest that such transfer may also take place in vivo. It is still uncertain whether proteins distinct from PrP can trigger a true “propagation” of misfolding in the manner of prions – that is, whether aggregated species released from one cell and taken up by another will lead to further aggregation of natively folded species in the recipient cell, and so on. The cellular mechanisms of aggregate release and uptake remain to be elucidated, and it will need to be determined whether the same mechanisms apply to all aggregation-prone proteins. Similarly, the true spectrum of these phenomena in other neurodegenerative diseases associated with protein misfolding is unknown. For example, will TDP-43 or SOD-1, which are both associated with amyotrophic lateral sclerosis, also exhibit such cell to cell transfer? It is also unknown what role glia and proposed cellular mechanisms might play in vivo. Can transfer of aggregates occur across synapses, and can this account for the propagation of pathology along neural networks? As the current studies are extended and augmented by existing knowledge of prion pathogenesis, a new unifying model that melds cell autonomous and non-cell autonomous mechanisms of protein misfolding in neurodegenerative diseases seems likely.

Footnotes

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