View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Frontiers - Publisher Connector REVIEW ARTICLE published: 18 February 2015 CELLULAR NEUROSCIENCE doi: 10.3389/fncel.2015.00045 Legal but lethal: functional protein aggregation at the verge of toxicity Angelika Falsone and S. Fabio Falsone * Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria Edited by: Many neurodegenerative disorders are linked to irreversible protein aggregation, a process Rosanna Parlato, Ulm University, that usually comes along with toxicity and serious cellular damage. However, it is emerging Germany that protein aggregation can also serve for physiological purposes, as impressively shown Reviewed by: Daniel Kaganovich, Hebrew for prions. While the aggregation of this protein family was initially considered exclusively University of Jerusalem, Israel, toxic in mammalians organisms, it is now almost clear that many other proteins adopt Israel prion-like attributes to rationally polymerize into higher order complexes with organized Robert Weissert, University of physiologic roles. This implies that cells can tolerate at least in some measure the Regensburg, Germany accumulation of inherently dangerous protein aggregates for functional profit. This review *Correspondence: S. Fabio Falsone, Institute of summarizes currently known strategies that living organisms adopt to preserve beneficial Pharmaceutical Sciences, aggregation, and to prevent the catastrophic accumulation of toxic aggregates that University of Graz, Schubertstr. 1, frequently accompany neurodegeneration. 8010 Graz, Austria e-mail: [email protected] Keywords: amyloids, prions, proteotoxicity, neurodegenerative diseases, proteostasis regulators INTRODUCTION in the amyloid rye: heat shock proteins and proteolytic pathways), Low structural complexity is at the basis of highly diversified macroscopic protein misfolding manifestations prevail with molecular recognition, whereby one flexible protein region senescence, as attested by the occurrence of ageing-associated can bind to various heterogeneous ligands by conformational neurodegenerative disorders such as Parkinson Disease (PD), adaptation. Proteins can functionally benefit from binding Alzheimer Disease (AD), spongiphorm encephalopathies, or promiscuity for key regulatory processes such as signal amyotrophic lateral sclerosis (ALS), all of them displaying transduction, transcription, RNA processing and translation. unsoluble protein inclusions as a signature. Proteins situated on intersecting hubs of different pathways can undergo multifunctional interactions, functioning as molecular switches by means of conformational variability. However, the AMYLOID AGGREGATION benefits of conformational freedom come along with the menace STRUCTURAL PROPERTIES OF AMYLOIDS of protein misfolding and multifunctional failure. Although Irrespectively of the protein structure and the exact anatomic each living organism invests conspicuous amounts of energy for localization, one type of proteinaceous inclusions appearing in the the rescue or elimination of misfolded polypeptides, a possible CNS features some unifying histologic and biophysical hallmarks inability of the cell to cope with misfolded polypeptides inevitably classified under the term “amyloid”, consisting of (A) a fibrous, leads to a massive functional destabilization, whereby proteins non-branched morphology, (B) the ability to alter the spectral can either lose their original function (loss-of-function), or properties of the dyes Congo red and thioflavin T, and (C) they acquire an improper, and therefore mostly lethal function X-ray diffraction patterns typical of cross-beta structure. The (gain-of-function), eventually aggregating after the complete term was coined by German pathologist Rudolf Virchow during collapse of folding and clearance pathways. the characterization of masses in human brains described as The central nervous system (CNS) is particularly susceptible “corpora amylacea”. Virchow perceived the relationship between to protein misfolding, but the reasons of such selective neuronal amyloids and disease, when he addressed the problem of “amyloid vulnerability are still elusive (Saxena and Caroni, 2011). Although degeneration” (Virchow, 1855). Today, it is well established healthy adult neurons can manage proteostasis by standard that the appearance of amyloids is associated with a chronic folding and degradation routines (see Section Molecular catchers tissue degeneration of the brain, and although not restricted to this organ, our current understanding of misfolding diseases is invariably linked to amyloid-associated neurological brain Abbreviations: CNS, central nervous system; PD, Parkinson Disease; AD, disorders (For a detailed list of known amyloid diseases, we refer Alzheimer Disease; ALS, amyotrophic lateral sclerosis; FTD, frontotemporal to the classification of the International Society of Amyloidosis dementia; HD, Huntington Disease; aSyn, alpha-synuclein; Abeta, beta- Sipe et al., 2014). amyloid; prp, major prion protein; htt, huntingtin; PLR, prion-like region; SG, stress granules; hsp, heat shock protein; UPS, ubiquitin-proteasome Amyloid aggregation is stereotypically linked to conformati- system; CMA, chaperone–mediated autophagy; MA, macroautophagy; GAG, onal flexibility, which allows for structurally diverse polypeptides glycosaminoglycan; HSPG, heparan suphate proteoglycans. to fold from a native into an alternative structure of the same Frontiers in Cellular Neuroscience www.frontiersin.org February 2015 | Volume 9 | Article 45 | 1 Falsone and Falsone Functional amyloids chemical composition, but with high beta-sheet content, a stereotactic delivery of toxic tau seeds, which is sufficient to remarkable resistance against proteolytic and denaturing agents, initiate spreading of AD-like neurofibrillary tangles along a and the ability to self-associate into fibers of typical cross-beta spatially defined trajectory (Iba et al., 2013). In close analogy, structure (Eisenberg and Jucker, 2012). The pathway of this the injection of aSyn seeds into brains of healthy mice triggers association is dynamically variegated, highly perturbable, and the self-perpetuating polymerization of endogenous aSyn and sensitive to a repertoire of factors such as genetic mutations, the development of clinical symptoms of PD (Luk et al., 2012). small ligands, changes of the physico-chemical environment, In both cases, the sequential diffusion of proteotoxicity along or post-translational side chain modifications (Eichner and interconnected brain regions substantiates the theory of a staged Radford, 2011). The resulting heterogeneous multiplicity of evolution of PD and AD (Braak et al., 2006). With respect conformational intermediates differing in size, shape and stability to original prions, all these proteins have thus been attributed poses an obstacle in isolating and unambiguously categorizing “prion-like” or “prionoid” propagation properties. However, amyloid aggregates, especially these conformers among them complicating a pathologic interpretation is the occurrence which are believed to be proteotoxic (Eisenberg and Jucker, of different conformationally variable toxic species from the 2012), and which likely accumulate in low amounts somewhere same protein, with separate propagation behavior and distinct between native polypeptide and mature amyloid. Improved phenotypic manifestations of the same condition. Sanders et al. biophysical techniques can in part overcome these limitations, demonstrated that tau, the signature protein of tauopathies, and they are beginning to provide useful structural insights of forms biochemically and morphologically distinct oligomers amyloid folding intermediates. By combining rapid fluorescence accounting for different disease phenotypes, with AD inclusions techniques with NMR spectroscopy, Sarkar et al. measured showing the most homogenous composition (Sanders et al., conformational fluctuations of a short-lived, low-abundance AD- 2014). Similar has been shown for Abeta, the major component associated beta-amyloid (Abeta) oligomer (Sarkar et al., 2014). of AD amyloid plaques. Different patient-derived as well as They could pinpoint the dynamic structure of this oligomer synthetic species of Abeta display an individual transmission to a patchwork of amino acid segments which fold locally behavior, accumulation pattern, aggregate morphology, and before the transition into highly ordered amyloid filaments. chemical stability (Stöhr et al., 2014; Watts et al., 2014). Likewise, Röthlein et al. employed time resolved fluorescence Bousset et al., also reported of two differently toxic aSyn and computational calculations to obtain structural views of an conformers with separate propagation properties (Bousset et al., extremely unstable huntingtin (htt) amyloid filament (Röthlein 2013). Additional complexity rises from the ability of particular et al., 2014). amyloid aggregates to act as cross-nucleation seeds for other structurally unrelated proteins. Alpha-Synunclein (aSyn), the MOLECULAR PATHWAYS OF AMYLOID PROPAGATION major constituent of PD associated Lewy Inclusions, can initiate Amyloid folding has been coupled early to prion diseases the deposition of tau in primary neurons and transgenic (Prusiner et al., 1983), a type of devastating neurodegenerative mice (Guo et al., 2013), while TDP-43 amyloids can seed disorders that are transmitted by direct and self-sustained for Abeta fibril growth (Fang et