Propagating Sticky Matters: An Update on “Prion‐Like” Templated Misfolding in Neurodegenerative Disorders

Introduction

Having led the way for decades, research on prions—the infamous agents at the core of devastating infectious neurological diseases—has recently successfully spread to new territories. During the last decade, major neurodegenerative conditions including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, amyotrophic lateral sclerosis (ALS) as well as frontotemporal lobar degeneration (FTLD) have been causally linked to diverse biologically unrelated proteins such as beta‐amyloid, tau, alpha‐synuclein, huntingtin, SOD1, as well as TDP‐43, which—when misfolded—form β‐sheet‐rich, relatively protease‐resistant oligomers with a high propensity to build up amyloid‐like aggregates. Through a process termed “templated misfolding,” to describe the conversion of native soluble proteins via misfolding into insoluble aggregates, seeds of aggregated proteins are thought to self‐perpetuate into large aggregates (“seed‐nucleation”) either within neighboring neurons or glial cells, or the extracellular milieu. Sharing remarkable similarities with the “classical” conversion of cellular prion protein (PrP^C) into scrapie prion protein (PrP^SC), aggregated proteins finally kill their host or neighbor cells by mechanisms that remain subject of currently ongoing research [for review, see 2]. Interestingly, protein aggregation may not always be harmful, but, when ordered, even serve important biological functions. This notion is exemplified by cytoplasmic polyadenylation element binding protein (CPEB), for which ordered aggregation has been postulated to facilitate long‐term potentiation 8, and more recently by the MAVS protein, which forms prion‐like aggregates on the mitochondrial surface to trigger an RNA‐dependent innate immune response to viral infection 5.

Although several pathways to acquired toxicity, such as proteasome inhibition, oxidative stress and aggregate‐associated sequestration of essential cellular components, have been put forward, an alternatively held view is that, rather than being culprits, the large protein aggregates merely represent relicts of a protective cellular response while the main causative agent(s) go undetected. In fact, there is now significant evidence to suggest that tiny oligomeric complexes, which occur during templated misfolding, may be much more harmful than the giant protein aggregates that—for more than 100 years—have caught the attention of neuropathologists during the diagnostic work‐up of neurodegenerative diseases.

Although the last couple of years have seen exponential progress in our understanding of basic mechanisms in experimental settings at least, we are still in an urgent need to far better understand what might be triggering protein misfolding, aggregation, propagation and spreading of the pathology under natural conditions. Most likely, although sharing basic principles, these processes are significantly modulated in a disease‐specific manner. For instance, in the case of ALS, it has been postulated that the aggregation of the RNA‐binding protein TDP43, and possibly of FUS/TLS, within stress granules is promoted by RNA molecules acting as scaffolds 7.

Despite the lack of epidemiological data from relatives and caretakers of affected patients to suggest natural transmission (with the exception of Creutzfeldt–Jakob and other bona fide prionoses), the central question of whether common neurodegenerative disorders such as AD, PD, ALS or FTLD can be transmitted outside experimental settings through prion‐like infectious mechanisms remains to be answered. In other words, we still do not really understand what distinguishes infectious prion diseases from the above‐mentioned, far more common disorders, for which—so far—transmission has only been shown under experimental conditions and outside of any disease context.

With this Mini‐symposium, it is our intention to provide the readership of Brain Pathology with an update on recent developments in the field, focusing on the prion‐like mechanisms of templated misfolding, which underlies the pathogenic process of various neurodegenerative (and other) diseases.

Starting with a historical account, Kretzschmar and Tatzelt 6 summarized our current understanding of prion diseases by first taking us through the biogenesis and maturation of the PrP^C. They extend their scope by discussing the link between aberrant folding and toxicity by exploring potential mechanisms of PrP^SC toxicity and considering transmission barriers in sporadic, familial and acquired human prion diseases.

Eisele 3 focused her account on prion‐like templated misfolding and seeded nucleation as fundamental mechanisms underlying the conversion of soluble beta‐amyloid into progressive aggregates as it occurs during the early phases of Alzheimer's disease. Having far‐reaching implications for protein misfolding disorders in general, basic tenets of this concept have, in the case of AD, already been translated into clinical trials aimed at interfering with beta‐amyloid aggregation at preclinical or early stages of the disease.

Clavaguera et al  1 reviewed recent research developments in the tauopathy field, putting a special focus on what might cause initiation and propagation of the tau pathology that is observed upon seeding of tau‐containing extracts into mouse brain. A deeper understanding of these processes may not only be key to understanding the stereotypical temporo‐spatial spreading pattern of tau pathology in the context of AD, but might also provide aid with the rationale design of strategies to inhibit tau disease progression.

Lastly, spurred by the observation of Lewy body‐like pathology that developed in normal neuronal stem cells, which had been transplanted more than a decade ago into the brains of PD patients, research into prion‐like mechanisms in synucleinopathies took on speed. Providing their perspective on the pathogenesis of synucleinopathies, George et al  4 review recent in vitro and in vivo studies aimed at exploring cell‐to‐cell transfer mechanisms for alpha‐synuclein and also reflect on how alpha‐synuclein pathology spreads within the nervous system.

This cluster of articles, contributed by leading investigators with expertise in specific protein misfolding‐associated neurodegenerative conditions, should provide a state‐of‐the‐art overview on this increasingly prevalent group of diseases. It is anticipated that the continued characterization of the critical steps during initiation, propagation and spreading of prion‐like protein misfolding will pin‐point novel targets for therapies to slow down, stop or even partly reverse the pathology of these relentlessly progressing disorders.

Conflict of Interest

The authors declare that they have no conflict of interest related to this article.