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Assembly of Protein Aggregates in Neurodegeneration: Mechanisms Linking the Ubiquitin/Proteasome Pathway and Chaperones

, , , and *.

* Corresponding Author: Department of Biological Sciences, Hunter College of CUNY, New York, New York, U.S.A. Email: pereira@genectr.hunter.cuny.edu

In recent years, it has become increasingly evident that the majority of neurodegenerative disorders is associated with the aggregation and deposition of proteins in inclusion bodies. To avoid this abnormal deposition of proteins the cells recruit molecular chaperones to suppress aggregation and the ubiquitin/proteasome pathway (UPP) to remove the aggregate-prone proteins. The UPP is the major nonlysosomal degradation pathway for intracellular proteins. UPP impairment and/or its overload are likely to be major contributors to the aggregation of ubiquitinated proteins detected in most neuronal inclusion bodies. The mechanisms leading to the formation of inclusion bodies are not well defined. In this chapter, we discuss cellular strategies to deliver substrates to the UPP and their potential contribution to the development of intracellular proteins aggregates. In the future, a better understanding of the steps leading to protein aggregation and their deposition in inclusion bodies is likely to provide opportunities for effective therapeutic interventions.


Proteolysis is an important cellular event involving tightly regulated removal of unwanted proteins and retention of those that are essential. In addition to its function in normal protein degradation, the ubiquitin/proteasome pathway (UPP) plays a critical role in the quality control process. The UPP eliminates mutated or abnormally modified proteins by degradation to prevent their accumulation as aggregates that often form intracellular inclusion bodies.

Intracellular inclusion bodies containing ubiquitinated proteins are detected in a variety of degenerative diseases. These diseases range from neurological disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and spinocerebellar ataxias, to liver diseases, such as Wilson's disease and alcoholic hepatitis, to name a few.1 Whether these inclusion bodies are pathogenic or represent a coping mechanism to prolong survival of the affected cells, such as neurons and hepatocytes, is a hotly debated issue. The abnormal protein aggregates, however, are indicative of a malfunction of the process of protein turnover since they are not prevalent in healthy individuals.

The major structural components of inclusion bodies vary from cell type to cell type. For example, microtubule associated tau proteins are found in cortical neurofibrillary tangles, α-synuclein in dopaminergic Lewy bodies and huntingtin in nuclear inclusions in the striatum (reviewed in ref. 2). However, most of these protein deposits contain ubiquitinated proteins. The massive neuronal deposition of ubiquitinated proteins in inclusion bodies in neurodegenerative disorders implicates the UPP in their formation. It is likely that these protein aggregates develop when the capacity of the proteasome as well as that of molecular chaperones is exceeded by the production of aggregation-prone misfolded proteins. The mechanisms leading to the formation of these protein aggregates remain to be fully characterized. In an effort to provide a general overview of the current information available on this topic, we will address the following issues: (1) Protein degradation by the UPP; (2) Potential mechanisms for the formation of ubiquitin-protein aggregates; (3) Subcellular distribution of ubiquitin-protein aggregates. This review will end with (4) Conclusions. Please note that this review is not intended to be comprehensive and we apologize to the authors whose work is not mentioned here.

Protein Degradation by the UPP

The proteolytic mechanism of the UPP has a broad specificity, cleaving peptide bonds after basic, acidic and hydrophobic amino acids. This pathway requires most proteins to be tagged by ubiquitin for proteasomal targeting. However, there is a small set of proteins, such as ornithine decarboxylase, that is targeted for proteasomal degradation by ubiquitin-independent means (reviewed in ref. 3). Besides ubiquitination, recent studies established that folded proteins require an additional targeting signal for efficient proteasomal degradation.4 Indeed, an unstructured initiation site on the protein substrate significantly accelerates its degradation by the proteasome.

In general, proteolysis by the UPP involves two major steps: ubiquitination followed by degradation. A de-ubiquitination step also plays important roles in this pathway as it edits the ubiquitination state of the different substrates and removes the ubiquitin tag for recycling.


Ubiquitin (Ub) is a small protein of 76 amino acids and it can form polyubiquitin chains. To target proteins for proteasomal degradation, polyubiquitin chains are formed by the successive attachment of monomers by an isopeptide bond formed between the side chain of Lys48 in one ubiquitin and the carboxyl group of the C-terminal Gly76 of a neighboring Ub. Attachment of polyubiquitin chains to lysine residues on a protein results in at least a 10-fold increase in its degradation rate.5 Polyubiquitin chains with linkages involving lysine residues other than Lys48 on ubiquitin, were found to play distinct roles. These alternate polyubiquitin chains play a role in DNA repair, activation of NF-κB, polysome stability and endocytosis, to name a few.6

Polyubiquitination of proteins is a complex process involving four steps (Fig. 1). The first step involves the formation of a high-energy thioester bond between Ub and a ubiquitin-activating enzyme (E1) in a reaction that requires ATP hydrolysis. In the second step a thioester bond is formed between the activated ubiquitin and ubiquitin-conjugating enzymes (E2). In the third step the carboxyl terminal of Ub is covalently attached to the protein substrate. This reaction is mediated by ubiquitin ligases (E3), which confer substrate specificity to the UPP. In general, the first ubiquitin conjugated to a protein is attached to the εamino group of substrate lysines via an isopeptide bond. However, recent findings demonstrated that ubiquitin can also be conjugated to the α-amino group of the N-terminal residue (reviewed in ref. 7) or to intramolecular cysteines of the substrate.8 In some cases, ubiquitin can be transferred directly to the protein substrate by ubiquitin-conjugating enzymes (E2). In the fourth step, multiubiquitin chains are assembled by a family of ubiquitination factors (E4) that produces longer Ub-chains.9

Figure 1. Protein ubiquitination.

Figure 1

Protein ubiquitination. First, a high-energy thioester bond is formed between ubiquitin (Ub) and a ubiquitin-activating enzyme (E1). This reaction requires ATP hydrolysis. Secondly, the activated ubiquitin is transferred to a ubiquitin conjugating enzyme (more...)

While the number of distinct E1 enzymes is small, there are many E2 and E3 enzymes, indicating that this pathway operates through selective proteolysis (reviewed in ref. 10). At least 50 E2s were identified in humans.11 They share a common 150-amino acid catalytic core, whereas each subfamily possesses affinity for a different class of E3 enzymes. E3s recognize specific protein substrates for ubiquitination and coordinate the ligation of ubiquitin to the substrate. The human genome contains at least 1,000 different E3s, providing high specificity to the UPP.7 Mechanistically, two classes of E3s have been described (reviewed in ref. 11). One class, the HECT-domain E3s,12 have a conserved Cys residue that participates in the transfer of activated ubiquitin to a target protein. The HECT-E3s form ubiquitin-thioester intermediates and ubiquitinate substrates directly. The second class of E3s is not catalytic. Instead, these E3s stabilize a molecular scaffold for E2 interaction with the substrate. The E2 will then ligate ubiquitin to the substrate. Some of these E3s consist of just one subunit (RING finger domain E3s) and others are multi-subunit complexes (SCF-type E3, VBC-Cul2 E3, anaphase promoting complex, to name a few).

The assembly of polyubiquitin chains can be a processive reaction requiring E1, E2 and E3 enzymes. In many instances, another enzyme is recruited that provides for a more efficient polyubiquitin chain assembly. These polyubiquitin elongation factors are collectively known as E4s (reviewed in ref. 13). So far, three types of E4s have been identified. The first type includes the U-box-containing E4s. The U-box is a 70-residue domain structurally related to the E3 RING-finger domain. One example of this E4 type is CHIP (C-terminus of Hsc70-interacting protein) a protein that is particularly relevant to neurodegeneration. Upon CHIP interaction with HSP90 and HSP70 it acts as an E3 ligase leading to the ubiquitination and proteasomal degradation of misfolded proteins that are chaperone-bound (reviewed in ref. 13, 14). CHIP in collaboration with the E3 ligase parkin, was also shown to act as an E4 elongation factor for the unfolded Pael receptor.15 The second type of E4s includes nonU-box E4s for which p300 is an example. This transcriptional cofactor was shown to attach polyubiquitin chains to p53 previously monoubiquitinated by the E3 ligase MDM2 (reviewed in ref. 13). Finally, the third type of E4s, so far only identified in C. elegans, consists of an E3-E4 polyubiquitinating complex (reviewed in ref. 13). In this case, two E3s, CHN-1 and UFD-2 act in concert as an E4, thus polyubiquitinating the myosin chaperone UNC-45.

Ubiquitin is removed from ubiquitinated proteins by de-ubiquitinating enzymes, which also disassemble polyubiquitin chains. More than 70 genes encoding for de-ubiquitinating enzymes have been identified in humans.16 There are two major classes of de-ubiquitinating enzymes. The first class, the ubiquitin carboxyl-terminal hydrolases (UCHs), removes small amides, esters, peptides and small proteins at the carboxyl terminus of ubiquitin. The second class, the ubiquitin-specific processing proteases (UBPs), disassembles the polyubiquitin chains and edits the ubiquitination state of proteins.17

Proteasome Degradation

One of the functions of covalently binding Ub to proteins is to mark them for degradation by the 26S proteasome (Fig. 2), a multicomponent enzymatic complex with a molecular mass of approximately 2,000 kDa.18 The 26S proteasome includes two major particles: a 20S particle, known as the 20S proteasome, which is the catalytic core, and a 19S particle, known as PA700, which is the regulatory component.

Figure 2. The 26S proteasome.

Figure 2

The 26S proteasome. Its two major particles, the 20S particle (20S proteasome) which is the catalytic core, and the 19S particle (PA700) which is the regulatory component, require ATP hydrolysis to assemble into the 26S proteasome. The crystal structure (more...)

The 20S particle is composed of 28 subunits arranged in four heptameric-stacked rings forming a cylindrical structure with a hollow center in which proteolysis takes place.19 The 20S proteasome hydrolyzes most peptide bonds present in a protein,20 and its rate of hydrolysis is influenced by its subunit composition.21 Assembly of this particle from precursor subunits is a complex process and requires the assistance of a short-lived chaperone.22

The 19S particle contains at least 15 subunits, including ATPases, a de-ubiquitinating enzyme and polyubiquitin-binding subunits. It confers ubiquitin/ATP-dependency to proteolysis by the 26S proteasome.18 The subunits in the 19S particle are distributed into a lid and base arrangement, with the lid required for ubiquitin/ATP-dependent peptide bond hydrolysis.23 The base containing the ATPases exhibits chaperone-like activity.24

Association between the two particles in the cell is a dynamic process and requires ATP-hydrolysis. The 20S proteasome can associate with other regulatory members, such as PA28, but this combination is not known to regulate the degradation of polyubiquitinated proteins.18

The 26S proteasome is found in the cytoplasm next to intermediate filaments of the cytoskeleton. 25 It also resides in the nucleus and in association with the cytoplasmic side of the ER membrane.26,27 Localization studies with fluorescently labeled subunits of the 20S and 19S particles demonstrated that proteasomal proteolysis occurs mainly at the nuclear envelope/rough ER site.28 An important function of such proteolysis is to eliminate abnormal secretory proteins residing in an ER/preGolgi compartment.29 Functionally inefficient, misfolded or unassembled ER proteins leave this intracellular compartment by retrograde transport through the Sec61 translocation channel. They are ubiquitinated by ubiquitin-conjugating enzymes associated with the cytosolic side of the ER membrane and then degraded by the cytosolic 26S proteasome.29 Although this ER degradation pathway appears to be nonessential for viability, its importance is underscored by its evolutionary preservation “despite strong negative selection” since disruption of this mechanism seems to be associated with many disease states.29

Potential Mechanisms for the Formation of Ubiquitin-Protein Aggregates

The role of inclusion bodies in the progression of neurodegeneration is unknown.30 On the one hand inclusions may be beneficial and result from an attempt of the cell to isolate a subclass of ubiquitinated proteins that are not effectively degraded. On the other hand, the inclusions may impede normal cell function contributing to cell death. The size and abundance of the inclusions maybe critical determinants of their toxicity.31 Accordingly, small inclusions may be protective while expanded inclusions may confer fatal effects that can contribute to neuronal cell damage.

Several mechanisms leading to the formation of intracellular aggregates of ubiquitinated proteins have been proposed. We will discuss four of them that may be relevant to the development of inclusion bodies in neurodegenerative disorders.

UBA/UBL “Noncanonical” Chaperones

The first mechanism involves “noncanonical” chaperones that deliver ubiquitinated proteins to the 26S proteasome. These potential shuttles for polyubiquitinated proteins (Fig. 3) contain an ubiquitin-like (UBL) domain at the N-terminus and at least one ubiquitin-associated (UBA) domain at the C-terminus (reviewed in ref. 32,33). The UBL domain is known to interact with the 19S particle of the proteasome, in particular with the subunit S5a/Rpn10.34 The UBA domain noncovalently binds polyubiquitin chains up to 300-times more tightly than mono-ubiquitin (reviewed in refs. 35, 36).

Figure 3. UBL/UBA proteins.

Figure 3

UBL/UBA proteins. These “noncanonical” chaperones exhibit a UBL (ubiquitin-like) domain at the N-terminus and at least one UBA (ubiquitin-associated) domain at the C-terminus. These proteins are thought to shuttle polyubiquitinated proteins (more...)

In the context of neurodegeneration one of the UBL/UBA proteins that is best characterized is the sequestosome1, also known as p62, first identified in human tissues by Shin and colleagues.37 The sequestosome1/p62 was detected in ubiquitin-containing intraneuronal and intraglial inclusions in a variety of neurodegenerative disorders38-41 as well as in hepatocyte Mallory bodies associated with alcoholism.42 These findings suggest that the sequestosome1/p62 is relevant to the biogenesis of inclusions containing ubiquitinated proteins. Furthermore, sequestosome1/p62 expression in neuronal cells is induced by serum withdrawal conditions that trigger apoptosis, by expression of expanded pathologic polyglutamine repeats43 and by proteasome inhibitors44,45 as well as prostaglandins of the J2 series.46 Due to its high affinity for polyubiquitin chains, sequestosome1/p62 was suggested to serve as a receptor for binding and storing ubiquitinated proteins.47 Recent studies with isolated HEK cells transfected with full-length or truncated sequestosome forms, indicate that sequestosome1/p62 may act as a shuttle that delivers polyubiquitinated proteins to the proteasome.34 Interestingly, these studies suggest that sequestosome1/p62 can bind polyubiquitin chains through the C-terminal UBA domain and the proteasome through its AID (acidic interaction domain), which is closer to the N-terminus. The AID is proposed to be structurally similar to ubiquitin-like (UBL) domains known to interact with the proteasome. Due to its binding versatility, the sequestosome1/p62 may play an important role as a scaffold and/or shuttle molecule storing polyubiquitinated proteins and delivering them to the proteasome in a regulated manner.

The discovery of proteins with UBL/UBA domains supports the view that translocation of ubiquitinated proteins to the proteasome is a regulated, not a stochastic process. This “shuttling” mechanism is likely to include not only UBL/UBA proteins but also other factors. For example, one of the proteins (ataxin 3) that cause polyglutamine-neurodegenerative diseases, exhibits the ability to bind polyubiquitin chains and de-ubiquitinating activity as well.48 Both ataxin 3 activities are required for the formation of protein aggregates.49 Another polyglutamine-neurodegenerative protein, ataxin 1, disrupts the interaction of the UBA/UBL protein A1UP with the 26S proteasome.50 To make matters more complex, some UBA/UBL proteins in yeast were shown to inhibit the degradation of model polyubiquitinated substrates.51 Delivery of ubiquitinated proteins to the proteasome is thus still poorly understood and remains an exciting future challenge.

The sequestration of polyubiquitiated proteins by the sequestosome1/p62 or other UBL/ UBA proteins could act as a cellular defense mechanism. Cellular stress conditions yielding large quantities of misfolded/polyubiquitinated proteins would benefit from their sequestration by these “noncanonical” chaperones. Up-regulation of these “noncanonical” chaperones triggered by increased levels of misfolded proteins would prevent them from blocking the proteasome. The latter would provide an efficient mechanism to regulate substrate access to the proteasome and prevent its shutdown by excessive amounts of substrates. These types of intracellular storage aggregates would thus prevent cell damage and promote cell survival. However, under extreme stress conditions the overabundance of misfolded proteins could jeopardize the delivery process and activate cellular death pathways.


The second mechanism leading to the formation of aggregates of ubiquitinated proteins involves aggresomes, first described by Kopito's group.52 Aggresomes are thought to be deposition sites for ubiquitinated proteins that escape degradation by the UPP (Fig. 4). They are cytoplasmic inclusions found in an indentation of the nuclear envelope that colocalizes with centrosome/MTOC (microtubule organizing center) markers (reviewed in ref. 53). Notably, previous studies demonstrated that the microtubule “minus end” motor activities directed by dynein are necessary for the formation of aggresomes,54 which also contain dynein.55 Dyneins direct intracellular cargos toward the cell center (and nucleus) where the microtubule “minus ends” are clustered at the MTOC.56 While some studies suggest that the retrograde transport of ubiquitin protein aggregates to centrosomes is dependent on microtubule integrity,52 others indicate that this process may not require intact microtubules.57

Figure 4. Aggresomes.

Figure 4

Aggresomes. Aggresomes result from the microtubule-dependent retrograde transport of small aggregates of ubiquitinated proteins to the area of the microtubule-organizing center (MTOC). The aggregates are shuttled by dynein complexes on microtubule tracks. (more...)

Aggresomes are composed of insoluble material and are associated with high levels of 26S proteasomes as well as with de-ubiquitination activity.57 Some of the ubiquitinated proteins shown to be deposited in aggresomes resulted from either overexpression of mutant cystic fibrosis transmembrane conductor regulator or presenilin 1 and/or from impaired protein degradation induced by treating cells with proteasome inhibitors.52,54,58

Currently, it is not clear if the mechanisms shown to participate in the formation of aggresomes occur under homeostatic and/or nonhomeostatic conditions. Aggresome-formation was demonstrated to occur mainly as a result of overexpression of mutant proteins in cells often treated with proteasome inhibitors. Therefore, aggresome formation has not been demonstrated in vivo.


A third mechanism leading to the formation of aggregates containing ubiquitin-conjugates was identified in maturing dendritic cells by Pierre's group.59 These transient (reversible) aggregates of ubiquitinated proteins (Fig. 5) are distinct from aggresomes. They are not colocalized with MTOC markers, they don't exhibit vimentin cages and they do not inhibit the proteasome.60 Upon stimulation with pro-inflammatory agents followed by treatment with protein damaging agents, the ensuing defective ribosomal products (DRiPs) are sorted into large cytosolic aggregates known as dendritic cell aggresome-like induced structures (DALIS). DALIS contain many components of the ubiquitination machinery, including E1, E2s and E3s. When DRiPs are formed they are rapidly sequestered into DALIS where they are eventually ubiquitinated. This mechanism allows dendritic cells to regulate the degradation rate of DRiPs, an ability that is pivotal to their immune functions.60 DALIS, are thus thought to act as antigen storage structures allowing for the regulated degradation of proteins during infection. Recent studies demonstrated that DALIS-formation is also induced in dendritic cells by heat shock61 and in macrophages by microbial products.62

Figure 5. DALIS.

Figure 5

DALIS. Defective ribosomal products (DRiPs) are considered a main source for MHC class I-restricted antigenic peptides. DRiPs are incorporated into dendritic cell aggresome-like induced structures (DALIS) where they are ubiquitinated and transiently stored (more...)

DALIS-formation requires continuous protein synthesis.60 It is thus tempting to speculate that up-regulation of UBL/UBA proteins may play a role in the sequestration of DRiPs into DALIS. However, the mechanisms involved in sorting DRiPs into DALIS and how DALIS are disassembled, remain to be characterized. Furthermore, if a DALIS-like sorting of defective and/or mutated proteins occurs in neuronal cells leading initially to transient aggregates, remains to be established. It is tempting to propose that overproduction of neuronal defective proteins and/or UPP impairment, disturb the DALIS-sorting mechanism resulting in permanent nonreversible aggregates such as the ones detected in neurodegeneration.

Russell Bodies

The fourth and final mechanism relevant to the formation of protein aggregates (in this case, of nonubiquitinated proteins) is related to the endoplasmic reticulum (ER) (reviewed in ref. 63). The ER aggregates known as Russell bodies were first discovered more than 100 years ago in cancer cells by Russell.64 More recently, Russell bodies were described as being swollen ER cisternae that contain insoluble aggregates of mutant immunoglobulin.65 They are postulated to form as a cellular attempt to compartmentalize abnormal ER proteins that cannot escape into the cytoplasm to be degraded (Fig. 6). Instead, they are sequestered into ER subcompartments to prevent blockage of the normal secretory pathway.65

Figure 6. Russell bodies originate from RER (rough endoplasmic reticulum) subcompartments containing nonsecreted proteins that escape intracellular proteolysis.

Figure 6

Russell bodies originate from RER (rough endoplasmic reticulum) subcompartments containing nonsecreted proteins that escape intracellular proteolysis. These nondegradable proteins fail to be translocated into the cytoplasm through the Sec61-based channel. (more...)

No Russell bodies were yet identified in neurons. In addition, Russell bodies do not contain ubiquitinated proteins as the ubiquitination machinery is absent from the ER lumen. Thus no correlation has been established between this ER sorting mechanism and the aggregation of ubiquitinated proteins detected in neurodegenerative diseases. However, this type of ER sequestration response may be relevant to the aggregation of proteins that, although nonubiquitinated, are residents of the secretory pathway and relevant to neurodegeneration.

Subcellular Distribution of Ubiquitin-Protein Aggregates

The intracellular aggregates containing ubiquitinated proteins detected in neurodegenerative disorders, vary in their subcellular distribution. Some are detected in the cytoplasm, such as in Parkinson's disease and others in the nucleus, such as in Huntington's disease. The cause of this differential subcellular aggregate distribution is not clear. An investigation of the nuclear diffusion limit in mammalian cells, including primary neuronal cells, established that large molecules (molecular masses above 70kDa) cannot freely diffuse into nuclei of intact, healthy cells.66 It is probable that many of the ubiquitin protein conjugates detected in inclusion bodies have molecular masses above 70kDa as estimated by western blot analysis. It is unlikely that these high molecular mass ubiquitin conjugates passively diffuse from the cytoplasm into the nucleus and vice-versa. The large aggregates could only passively enter the nucleus if the nuclear membrane was disrupted. Accordingly, nuclear migration of full-length mutant huntingtin can only occur upon deterioration of the nuclear membrane.66 Wild type huntingtin is a cytoplasmic protein with a molecular mass of ˜350kDa. Neither wild type nor mutant huntingtin have a nuclear targeting signal and thus cannot be actively transported across the nuclear membrane.66 Interestingly, the subcellular distribution of transfected GFP (˜30kDa) fused to full length or truncated forms of wild type or mutant huntingtin is not homogeneous. These fusion proteins can accumulate in the cytoplasm, nucleus or both, depending on the size of the fusion protein, on the nuclear diffusion limit of the specific transfected cells and on their nuclear membrane integrity.66 We conclude that aggregate size, nuclear diffusion limit and nuclear membrane integrity are some of the factors that determine the subcellular distribution of protein aggregates.

Concluding Remarks

Evidence implicating molecular chaperones in neurodegenerative diseases is more compelling than that for the UPP, mainly because a direct link between UPP impairment and neurodegeneration is next to impossible to prove in postmortem human tissue. However, studies with human disease tissue indicate that disturbances of protein degradation by the UPP must have catastrophic consequences and play a critical role in neurodegeneration. It is clear that a full-cooperation between the proteolytic and chaperone systems is required to prevent the development of potentially toxic protein aggregates. The UPP is recruited for removal of proteins that are most likely modified, misfolded, ubiquitin-tagged and that escape appropriate refolding by molecular chaperones. However, the overwhelming production of misfolded proteins alone or in conjunction with UPP impairment is likely to lead to the formation of protein aggregates most of them containing ubiquitinated proteins. We are just beginning to decipher the intracellular mechanisms (some of them described above) that contribute to protein aggregation. A better understanding of this process will most certainly lead to new routes for therapy.


This work was supported by National Institutes of Health Grants NS34018 (M.E.F.-P.) as well as GM60654 (NIGMS) and RR03037 (NIGMS/RCMI core facility grant) both to Hunter College of CUNY.


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