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© 2012 John Wiley & Sons A/S doi:10.1111/j.1600-0854.2012.01330.x
Review
Quality Control Compartments Coming of Age Tziona Ben-Gedalya and Ehud Cohen∗ Biochemistry and Molecular Biology, The Institute for Medical Research Israel – Canada (IMRIC), The School of Medicine of the Hebrew University of Jerusalem, Jerusalem 91120, Israel *Corresponding author: Ehud Cohen,
[email protected] Maintenance of proteome integrity (proteostasis) is essential for cellular and organismal survival. Various cellular mechanisms work to preserve proteostasis by ensuring correct protein maturation and efficient degradation of misfolded and damaged proteins. Despite this cellular effort, under certain circumstances subsets of aggregation-prone proteins escape the quality control surveillance, accumulate within the cell and form insoluble aggregates that can lead to the development of disorders including late-onset neurodegenerative diseases. Cells respond to the appearance of insoluble aggregates by actively transporting them to designated deposition sites where they often undergo degradation. Although several protein aggregate deposition sites have been described and extensively studied, key questions regarding their biological roles and how they are affected by aging remained unanswered. Here we review the recent advances in the field, describe the different subtypes of these cellular compartments and outline the evidence that these structures change their properties over time. Finally, we propose models to explain the possible mechanistic links between aggregate deposition sites, neurodegenerative disorders and the aging process.
structure and damaged mature proteins are designated for degradation by either the ubiquitin proteasome system (UPS) (4,5) or by the lysosome via one of the autophagy pathways (6). Despite the activity of the proteostasis machinery, under certain circumstances aggregation-prone proteins misfold, escape degradation and form insoluble aggregates. The accumulation of protein aggregates is mechanistically linked to the development of various disorders that were collectively termed ‘conformational diseases’ (7,8). A prominent subset of these maladies is the group of lateonset neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s (PD) disease (9), Huntington’s disease (HD)(10), amyotrophic lateral sclerosis (ALS) (11) and prion disease (12). Because of the hazardous potential of protein aggregates (proteotoxicity), disaggregation mechanism acts to disintegrate and prepare them for degradation by the UPS (13), by proteases (14,15) or in some cases by autophagy (16,17). When these aggregate clearance mechanisms are overtaxed or malfunction, potentially deleterious aggregates accumulate within the cells which respond to the challenge by actively transporting and confining them in designated deposition sites. Accordingly, aggregate deposition sites are the hallmark features of various neurodegenerative diseases (9,12,18).
Key words: aging, degradation, deposition site, neurodegeneration, protein aggregation, quality control
Protein Aggregate Deposition Sites in Neurodegenerative Disorders
Received 14 November 2011, revised and accepted for publication 19 January 2012, uncorrected manuscript published online 23 January 2012, published online 16 February 2012
Aggregate deposition sites associated with distinct maladies exhibit different features. AD, the most prevalent neurodegenerative disorder that affects memory and cognition (reviewed in 19), stems from the double proteolytic digestion of the amyloid precursor protein that releases a family of aggregation-prone peptides which were collectively termed amyloid β (Aβ) peptides. Aβ aggregates are deposited in extracellular plaques in the brains of patients with Alzheimer’s disease (19) and of AD model mice (20). An additional pathological hallmark of AD is the intracellular presence of neurofibrillary tangles containing hyperphosphorylated, insoluble microtubuleassociated protein, Tau (19).
Maintaining the integrity of the proteome in the face of constant challenges is vital for cellular and organismal function and survival. Multiple biological mechanisms work in concert to create and sustain accurate protein synthesis and posttranslational modifications, correct folding and localization of the nascent molecules as well as exact protein–protein interactions. This continuous quest for a precise protein network was termed ‘proteostasis’ (1). Proteostasis is steadily maintained in different cellular organelles by specialized mechanisms. Sets of molecular chaperones assist newly synthesized polypeptides to fold and mature properly in the cytosol (reviewed in 2) and in the endoplasmic reticulum (ER) (3). Newly synthesized polypeptides which failed to attain their desired spatial
The pathological hallmark of PD, a disease that mainly affects dopaminergic neurons of the central nervous system which are involved in the control of movement, (21,22) is the cytosolic inclusion known as ‘Lewy body’ (LB) (23). LBs are mainly composed of aggregated www.traffic.dk 635
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α-synuclein (24), attract molecular chaperones and proteasomes (25) and react with ubiquitin antibodies (26). HD which affects muscle coordination and cognition is caused by the aggregation of a mutated huntingtin protein that carries an abnormally long glutamine stretch (polyQ) (10). Huntingtin aggregates are deposited not only in the nucleus, but can also be found in the cytosolic perinuclear deposits (27). The aggregation of the prion protein (PrP) underlies the development of at least four distinct human neurodegenerative maladies: Creutzfeldt–Jakob disease (CJD), ¨ Gerstmann–Straussler–Scheinker syndrome (GSS), fatal familial insomnia and Kuru (reviewed in 12). Immunostaining of prion-diseased brains revealed that the toxic, infectious form of PrP (PrPSc ) creates filamentous-like amyloidal structures (28). While HD onsets solely as a mutation-linked disorder, some of these maladies emerge in more than one pattern. AD, PD, ALS and prion maladies mostly manifest as sporadic diseases; however, the minority of cases onset in a familial, mutation-linked fashion. A third form of emergence, clinically unique to the prion diseases Kuru and CJD, is by infection (12). Lately, prion-like properties have been attributed to disease-linked aggregation-prone proteins other than PrP. These features include cell to cell aggregate transmission (29) and faster appearance of Aβ plaques in the brains of transgenic AD model mice (but not in the brains of wild-type animals) following injection of AD brain extracts (30). Although thus far only prion diseases have been shown to be infectious, the possibility that other neurodegenerative disorders might be transmissible to susceptible patients should not be excluded (31). Although the linkage between aggregated protein inclusion bodies and neurodegenerative diseases was first described nearly a century ago (23,32,33), several key questions remained unanswered. These include: (i) is the accumulation of aggregates in deposition sites protective? or is it detrimental to the cell? (ii) are these structures ‘burial grounds’ for terminally aggregated proteins or perhaps they serve as quality control centers where protein aggregates are disintegrated and recycled? and (iii) what are the functional and biochemical differences among distinct types of deposition sites? As the identification of human neurodegeneration-linked deposition sites in brain tissues is possible exclusively postmortem, it was necessary to develop laboratory models to study the cell biological and metabolic features of aggregate deposition sites.
The Cell Biology of Protein Aggregates and Models for Cellular Deposition Sites In their seminal study, Wojcik et al. (34) treated cultured mammalian cells with a proteasome inhibitor and found 636
that this treatment resulted in the accumulation of dense material next to the cell nuclei. These dense structures were labeled by dyes that stain proteins but not by compounds that label lipids or nucleic acids. Immunolabeling by ubiquitin antibodies indicated that the dense juxtanuclear material contains ubiquitinated proteins. The inhibition of protein synthesis by the drug cycloheximide prevented the formation of these structures, and the disruption of microtubuli by the drug nocodazole induced the dispersion of these deposits. These observations indicated that upon UPS impairment, ubiquitinated protein aggregates are convoyed along microtubule to a cytosolic, perinuclear site which was termed a ‘proteolysis center’ (34). Johnston et al. (35) studied the fate of aggregative proteins by expressing the disease-linked, mutated, aggregationprone cystic fibrosis transmembrane conductance regulator (CFTRF508) in mammalian cells and following its intracellular localization. They discovered that upon either overexpression or proteasome inhibition, CFTRF508 aggregates accumulated in cytosolic deposition sites which they termed ‘aggresomes’ (35). Much like the proteolysis centers, aggresomes contain ubiquitinated proteins, are located next to the nucleus and their formation is disrupted by nocodazole. Detailed characterization revealed that aggresomes are formed at the microtubule organizing center (MTOC) and confined by collapsed intermediate filaments as visualized by a vimentin antibody. The formation of aggresomes was found to be a general cellular response to the accumulation of protein aggregates, as additional aggregative proteins accumulate in aggresomes in response to overexpression or UPS impairment, including the AD-linked, mutated presenilin-1 A246E (35), disease-causing PrP conformers (PrPSc ) (36), mutated, CJD-linked PrP molecules (37), fragments of mutated HDassociated, huntingtin (38), α-synuclein (16,39) and the synthetic chimera GFP-250 (40). Aggresomes, containing different aggregated proteins, were shown to attract molecular chaperones (25,40). The familial prion disease GSS is associated with the substitution of a proline in either P102 (41) or P105 (42) residue in the sequence of PrP. Studying the cell biological properties of GSS-linked, mutated PrP molecules, we discovered that like other aggregative proteins, proteasome inhibition results in the accumulation of these molecules in aggresomes. Interestingly, the inhibition of folding chaperone members of the cyclophilin family of proline cis/trans isomerases (43) by the drug cyclosporin A (CsA), but not treatment with proteasome inhibitors, has led to the accumulation of wild-type PrP molecules in aggresomes (CsA–PrP aggresomes) (44). Recently, we found that CsA–PrP aggresomes attract molecular chaperones and are formed despite intact proteasome activity. Furthermore, utilizing fluorescently tagged PrP and live-imaging techniques, we found that proteasomes participate in the clearance of aggresomeresident PrP molecules despite the lack of ubiquitinated
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molecules in these structures (45). This observation was in line with the finding that GFP-250 aggresomes attract proteasomes but do not react with ubiquitin antibodies (40) and indicate that proteasome inhibition or overloading are not prerequisites for the formation of aggresomes. It also shows that, in some cases, aggresome-resident molecules are cleared by proteasomes in a ubiquitinindependent manner. Autophagy was also reported to play roles in the clearance of aggresome-resident, disease-linked proteins including a mutated form of the polyQ-containing androgen receptor (46). However, the clearance of such proteins by autophagy was not shown to be a general phenomenon as this pathway is involved in the clearance of specific aggresome-resident proteins, but not of others (16). Collectively, the attraction of chaperones and proteasomes to aggresomes (25,40,45) as well as the disintegration of proteolysis centers (34) and PrP aggresomes (45) upon the inhibition of protein synthesis indicate that these deposition sites are dynamic quality control centers that enable the sequestration and degradation of potentially toxic aggregates in a controlled manner. This notion is also supported by the roles of autophagy in the clearance of aggresome-resident proteins. These findings raise the question of whether all cellular aggregate deposition sites serve as quality control centers or perhaps there are aggregate disposal structures that exhibit different cellular functions. In their pioneering study, Kaganovich et al. (47) aimed to explore the cellular aggregate detoxification pathways. They expressed fluorescently tagged, aggregation-prone proteins of different properties in yeast and mammalian cells and followed their fates. Intriguingly, they found that distinct protein aggregates are sorted to at least two types of deposition sites that can concurrently exist within a single cell (47). One of these sites is juxtanuclear, contains highly mobile proteins, functions as a dynamic quality control compartment and was accordingly termed ‘juxtanuclear quality control compartment’ (JUNQ). The JUNQ and the previously defined aggresomes share several key features including the attraction of proteasomes and molecular chaperones (40,45), high exchange rate with the cytosol (45) and localization in close proximity to the nucleus. In addition, like the proteins deposited in some types of aggresomes (35,36), proteins in the JUNQ are ubiquitinated (47). However, aggresomes and the newly defined JUNQ were not located next to the same cellular compartments. Unlike aggresomes which are localized at the MTOC, the JUNQ was not colocalized in close proximity to the yeast’s spindle pole body (analogous to the MTOC of mammalian cells) but instead was located in close proximity to the ER (47). The other type of aggregate deposition site has different properties. It contains non-ubiquitinated, immobile proteins and does not attract proteasomes. Apparently, this type of deposition site, which was termed ‘insoluble protein deposit’ (IPOD),
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accumulated terminally aggregated, non-degradable proteins (47). Similar to the JUNQ and unlike the aggresome, the IPOD was not found to colocalize with the spindle pole body. The colocalization of the fluorescently tagged, autophagy-related protein ATG8 with the IPOD (47) proposes that this deposition site is a pre-autophagosomal structure. The discovery and characterization of the proteolysis centers, aggresomes and of the JUNQ show that cells respond to the accumulation of degradable protein aggregates by the formation of dynamic quality control centers of several subtypes. The aggregates deposited in these sites are dispersed by molecular chaperones and eventually degraded by proteasomes. Non-degradable aggregates are directed to terminal aggregation deposits (IPOD) and presumably digested by the autophagosomal pathway. Accumulating data propose that quality control centers such as aggresomes, JUNQ and IPODs mimic the deposition sites associated with neurodegenerative disorders. First, PrPSc containing aggresomes were observed both in cultured cells and in the brains of prion-infected mice (36). Moreover, LBs found in the brains of patients with PD share important features with aggresomes and with JUNQ including juxtanuclear localization, the attraction of proteasomes and molecular chaperones (25) as well as reaction with ubiquitin antibodies (26). These similarities suggest that these structures protect cells from proteotoxicity by mediating the degradation of their content by the UPS. Likewise, autophagy has been shown to play critical roles in the clearance of neurodegeneration-linked protein aggregates (48) implying that this pathway is also essential for protection from these disorders.
Aggregate Deposition Sites and Neurotoxicity Several lines of evidence indicate that aggregate’s deposition sites are protective structures rather than sources of toxicity. The finding that the number of extracellular Aβ plaques and the severity of AD do not correlate (49,50) raised the question: what are the most toxic aggregative Aβ structures? Several studies have pointed at small oligomers as the most toxic Aβ species (reviewed in 51). Notably, Shankar et al. (52) not only indicated that Aβ dimers impair neuronal activity in vitro more efficiently than large fibrils, but also showed that breaking large Aβ fibrils of low toxicity into small oligomers reinstate high toxicity levels (52). Recently, it was shown that Aβ dimers rapidly assemble to form larger protofibrils which bear neurotoxicity (53). Although this study raised the prospect that not dimers but other small aggregative structures are the most toxic species, it reinforced the role of small structures, rather than large fibrils, as the major source of toxicity. It is important to note that, although probably less toxic than small structures, Aβ plaques also initiate neuritic changes and toxicity (54). In the light 637
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of the notion that large aggregative structures are less toxic than small oligomers, it is expected that cells will actively accelerate aggregation when the concentration of the toxic oligomers exceeds their clearance capacity or when the disaggregation machinery malfunctions. Shorter and Lindquist (55) reported that the yeast chaperone Hsp104 exhibits opposing protective activities. When the concentration of aggregates was relatively low, Hsp104 disassembled them; however, when the concentration exceeded a threshold level, it actively assembled them to create less toxic large aggregates (55). Similarly, a high concentration of small polyQ oligomers in mammalian cells activated the chaperone TRiC that acts in concert with HSP70 to assemble them into larger species of lower toxicity (56). To directly test the hypothesis that hyperaggregation and deposition of large aggregates are protective, Arrasate et al. (57) developed an automated microscopic technique and monitored the fates of rat striatal neurons that express fluorescently tagged, aggregative polyQ peptides. Cells which accumulated polyQ aggregates in inclusion bodies exhibited elevated survival rates compared to their counterparts that had no polyQ-containing inclusions (57). Additional support to the protective role of cellular deposition sites was obtained from the finding that cells containing LB-like α-synuclein inclusions exhibit elevated survival rates in comparison with cells that did not contain such inclusions (58). Furthermore, Aβ plaques were observed in postmortem brain tissues of aged healthy individuals (30) indicating that the presence of these deposits is not necessarily linked to disease. Together these studies indicate that the accumulation of protein aggregates in deposition sites protects cells from proteotoxicity. Why then are these cellular structures associated with disease?
Aggregate Deposition Sites and the Aging Process Late onset is a common feature of different human neurodegenerative diseases. While familial mutationlinked cases typically onset during the patient’s fifth or sixth decade, sporadic cases do not manifest earlier than the seventh decade of life. This shared temporal emergence pattern defines aging as the major risk factor for the development of these maladies (59). This raised the prospect that the aging process plays active roles in enabling the manifestation of neurodegeneration late in life. Studies on invertebrate models (60–64) and on mammals (65,66) have clearly indicated that slowing aging by reducing the activity of the highly conserved insulin/insulin-like growth factor (IGF) signaling pathway (67) protects from proteotoxicity and delays the development of disease. Interestingly, in AD model organisms this protection was foremost associated with Aβ hyperaggregation (60,65), supporting the theme that 638
this activity is protective. If both disaggregation and hyperaggregation are protective (60), what might be the cellular advantages of developing opposing, potentially competing aggregate detoxifying activities? We propose a three-stage model to explain the changing cellular counter-proteotoxic strategies over time (Figure 1A). In the first stage, early in life, the disaggregation and degradation mechanisms are highly efficient and capable of clearing toxic protein aggregates from the cell. This is the preferred pathway as it prevents proteotoxicity and enables the recycling of amino acids. It is plausible that the high competence of the disaggregation/degradation mechanisms prevents the emergence of neurodegenerative maladies in young individuals, even in those carrying disease-linked mutations (68) and in young AD model mice (69,70). Later in life, the aging process compromises the proficiency of the disaggregation/degradation machinery, enabling the accumulation of protein aggregates within the cell. The cell responds by the activation of a secondary protective mechanism, hyperaggregation, which assembles highly toxic oligomers into large aggregates of lower toxicity. This activity is accompanied by the confinement of these aggregates in deposition sites (Figure 1B) and their subsequent degradation. As a result of the lower counter-proteotoxic competence of the hyperaggregation/deposition mechanism, it cannot prevent the emergence of neurodegeneration in patients who carry disease-linked mutations and suffer from high aggregation burden. Consequently, these individuals typically develop familial disorders during the fifth or sixth decade of life. However, at this stage of life, the hyperaggregation mechanism can efficiently deal with the lower aggregation load exhibited by individuals who do not harbor such mutations, thus preventing the onset of sporadic cases of neurodegenerative maladies. The dual defense hypothesis is supported by several studies. First, we found that in Aβ worms the heat shock factor-1, which regulates disaggregation (60), promotes its counter-proteotoxic functions foremost during development, while DAF-16, which facilitates hyperaggregation (60), is needed during early adulthood and midlife (71). We also discovered that no plaques are present in the brains of young (up to 6 months of age) long-lived mice that harbor only one copy of the IGF-1 receptor. Later in life, these animals are protected from AD-like disease and exhibit elevated hyperaggregation and deposition of aggregates in plaques (65). While the prominent AD hallmark is Aβ extracellular plaques, intracellular Aβ-containing deposits are also present (reviewed in 72). In this regard, it would be interesting to study whether Aβ toxicity arises late in life from intracellular deposits, extracellular plaques or both. The postulated link between the aging process and aggregate deposition sites has been further established
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B
by a study which examined the postmortem brains of patients who received fetal dopaminergic neuron transplants as a novel cell-based therapy in order to mitigate the symptoms of PD. Surprisingly, the embryonic grafted neurons contained aggregated and ubiquitinated α-synuclein in LB pathology, 12, 14 and 16 years after transplantation (73,74). One possible explanation for this phenomenon proposes that α-synuclein aggregation in the host cells exhibits ‘prion-like’ features and initiates the misfolding, aggregation and deposition of this protein in the grafted cells. An alternative model suggests that the chronologically young neurons adapted to the biological age of their environment and activated a hyperaggregation program, which typically functions in old cells. This possibility is based on the assumption that cells receive environmental signals that can induce the activation of aging-associated biological functions. In the third stage of life, an aging-associated decline in the efficiency of the hyperaggregation/deposition mechanism exposes old cells to proteotoxicity and the aged organism succumb to disease. Three basic models can explain how deposition sites lose their protective roles over time. The first model (Figure 2A) proposes that aging steadily reduces the competence of hyperaggregation, preventing the assembly and sequestration of small, highly toxic oligomers from the cellular environment. According to this hypothesis, toxicity arises not from the deposition site but stems from small aggregative species that failed to be assembled and deposited. The second model (Figure 2B)
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Figure 1: A and B) Three-stage model for the development of neurodegenerative disorders. (I) Early in life, efficient disaggregation and degradation mechanisms clear toxic protein aggregates from the cell preventing disease and aggregate deposition. (II and B) At midlife, aging-associated decline in the competence of disaggregation leads to the activation of a secondary protective mechanism which hyperaggregates and deposits misfolded proteins in cellular deposition sites. (III) Late in life, malfunction of both protective mechanisms exposes the cell to neurotoxicity and subsequently to disease
suggests that the inclusion bodies that provide protection during midlife become the sources of toxicity late in life as they disintegrate and release toxic material to the cellular environment. According to the third model (Figure 2C), more than one subtype of aggregative material accumulates in cellular deposition sites. While most deposited molecules undergo degradation, a minority of highly toxic, non-degradable aggregates accumulate in the deposition site, changing its features over time. Late in life, the latter molecular subpopulation becomes the majority of the deposited material, gradually changing the properties of the deposition site from a protective quality control center into a source of toxicity. In our recent study (45), we tracked CsA–PrP aggresomes over time in living cells and discovered that at least two subpopulations of PrP aggregates accumulate in these deposition sites: degradable PrP aggregates and more stable structures. These findings support the idea that over time hazardous material accumulates in the aggresome turning this protective aggregate deposition site into a source of toxicity and disease. This process may be more deleterious in the brain due to the post-mitotic nature of most neurons and their alleged increased sensitivity to proteotoxicity. It is probable that a combination of these models is accountable for the development of neurodegeneration late in life. 639
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A
B
Figure 2: Three possible models for the development of neurotoxicity late in life. A) Reduced aggregation and deposition capabilities prevent the sequestration of highly toxic oligomers, exposing the cells to the proteotoxicity of the soluble toxic species which failed to be deposited at the deposition site. B) Aging-associated impairment of maintenance functions leads to the disintegration of the cellular deposition site releasing toxic structures from the deposit causing cell death. C) The concentration of nondegradable, highly toxic aggregate subpopulation reaches levels that turn the aggregate deposition site from a protective structure into a source of toxicity that overwhelms the cell.
C
Open Questions and Future Prospects Several biological questions have to be addressed in order to decipher the changing properties of aggregate deposition sites and their possible aging-associated dynamics. First, a detailed analysis of the content of deposition sites will enable the characterization of their molecular subpopulations. Such experiments could answer key questions including what cellular organelle each subpopulation originated from, what are their biochemical properties and whether cells are capable of detoxifying the different misfolded protein species. The creation of animal models which contain aggregate deposition sites and are amenable to aging manipulation will be useful and essential to explore the possible links between the aging process, the formation of aggregate deposition sites and their changing properties during the lifecycle. The nematode Caenorhabditis elegans offers a few advantages for the study of these questions. 640
Its transparency easily enables the use of imaging techniques, and the broad knowledge regarding the regulation of its aging program allows the research of the links between aging and quality control compartments. An additional model organism that offers remarkable advantages such as wealth of genetic tools for the study of aging and protein aggregation is the fruit fly Drosophila melanogaster . We believe that such models will be generated in the years to come and will shed new light on the properties of aggregate deposition sites and their mechanistic links with aging and disease.
Acknowledgments We thank Dr Daniel Kaganovich and Dr Alexander Rouvinski for critical reading of this manuscript. This study (45) was generously supported by the Rosalinde and Arthur Gilbert Foundation (AFAR) (E. C.) and by the National Institute for Psychobiology in Israel (NIPI) (E. C.). T. B. G. is supported by the Anonymous Foundation and by the Lady Davis trust.
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