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Masi, M.;  Attanzio, A.;  Racchi, M.;  Wolozin, B.;  Borella, S.;  Biundo, F.;  Buoso, E. Translation Impairment in Neurodegeneration. Encyclopedia. Available online: https://encyclopedia.pub/entry/37929 (accessed on 25 June 2024).
Masi M,  Attanzio A,  Racchi M,  Wolozin B,  Borella S,  Biundo F, et al. Translation Impairment in Neurodegeneration. Encyclopedia. Available at: https://encyclopedia.pub/entry/37929. Accessed June 25, 2024.
Masi, Mirco, Alessandro Attanzio, Marco Racchi, Benjamin Wolozin, Sofia Borella, Fabrizio Biundo, Erica Buoso. "Translation Impairment in Neurodegeneration" Encyclopedia, https://encyclopedia.pub/entry/37929 (accessed June 25, 2024).
Masi, M.,  Attanzio, A.,  Racchi, M.,  Wolozin, B.,  Borella, S.,  Biundo, F., & Buoso, E. (2022, December 05). Translation Impairment in Neurodegeneration. In Encyclopedia. https://encyclopedia.pub/entry/37929
Masi, Mirco, et al. "Translation Impairment in Neurodegeneration." Encyclopedia. Web. 05 December, 2022.
Translation Impairment in Neurodegeneration
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Protein synthesis is a strictly controlled molecular process because of its central role in different key cellular events, including homeostasis maintenance and response to extra- and intracellular cues. Increasing evidence suggests a dysfunction of the translation machinery in different neurodegenerative disorders. These dysfunctions are characterized by the accumulation of pathological protein aggregates, which could reflect defects in both ribosome and ribosome-associated activities.

Ribosome Dysfunction Ribosome Stalling Protein

1. Ribosome Dysfunction and Impaired Protein Synthesis

Several studies have reported that alterations or defects of protein synthesis may occur in AD [1][2]. In this regard, direct evidence from both mild cognitive impairment (MCI) and AD patients, particularly in brain areas involved in cognition, revealed a ribosomal dysfunction characterized by decreased protein synthesis and RNA alterations [3], while initiation factors levels were not altered in these same brain regions [4].
Emerging data suggest that translation elongation plays a role in AD onset and defects in protein synthesis compromise neuronal functions, favoring AD development by affecting the correct translation mechanism [5][6]. The microtubule-associated protein tau abundantly associates with ribosomes in human brains of AD patients compared to healthy brains, leading to a decreased translation. This aberrant association also impairs the synthesis of pivotal synaptic proteins, contributing to synaptic dysfunction. These pathological associations between tau and ribosomes in the AD brain results in a reduction in nascent proteins, including those required for synaptic plasticity, central for memory and learning. Therefore, this observation links the appearance of pathologic tau inclusions with cognitive impairments featured by all tauopathies, including AD and FTD [7]. In mouse models of FTD-tau—tauopathy caused by aberrant changes of tau—a mass spectrometric analysis revealed mutant tau-induced ribosome alterations and a decrease in specific ribosomal proteins (RPs), leading to a reduction in protein synthesis and ribosome biogenesis [8]. Altogether, these observations suggest that impaired ribosome functions may arise even after correct ribosome assembly and maturation, hampering protein synthesis and increasing neuron vulnerability [9]. In addition, oxidized ribosomes were shown to directly induce a decrease in protein synthesis [7][10]. In this regard, increased ribosomal RNA (rRNA) oxidation has been observed in early AD [3][11] and high levels of oxidized rRNA were found in 40S and 60S ribosomal subunits of MCI patients and in mature 80S ribosomes of AD patients. These same analyses showed decreased levels of ribosome precursors in MCI patients and reduced levels of mature ribosomes in AD patients [11]. Most oxidation-related RNA damage occurs in brain areas prominently exposed to AD pathology and, in early AD, this is concomitant with the onset of cognitive decline [12]. Therefore, RNA oxidation also seems to take part in the dysregulation of the translation apparatus in this pathology [13]. Moreover, according to the MODOMICS database, other RNA modifications on coding and non-coding RNAs have been identified, although only a few have been linked to neurological disease [14][15]. These include pseudouridine, adenosine methylation at position 1 (m1A, also known as N1-methyladenosine), 5-methyl cytosine (m5C), and N6-methyladenosine (m6A). In this regard, m6A modifications have been shown to play a role in different processes including learning memory, neurogenesis, and axon regeneration. The dysregulation of m6A pathways has been implicated in the onset of neurological diseases including AD, where m6A modifications at the 3′-UTR of mRNAs alters the translation of transcripts linked to age-related disease phenotypes [16]. In accordance, recent evidence showed a progressive m6A increase concomitantly with AD severity in human brains. Mechanistic studies demonstrate that oligomeric tau (oTau) is connected to m6A-modified transcripts via heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1), which functions as a linker. Indeed, both m6A and m6A-oTau-HNRNPA2B1 complex levels are highly increased in brains of AD patients and in the P301S tau mice model, indicating that this complex favors the integrated stress response towards oTau [17]. The reversible m1A is known to target both rRNAs and tRNAs. This modification, which has been correlated to the increased tRNA structural stability and its correct folding, is decreased in brain tissues from an AD mouse model, where this reduced m1A methylation could impact translation efficiency. Therefore, the observed dysregulation of the m1A modification could contribute to AD aetiology by affecting protein synthesis [18]. Finally, a reduced polyribosome activity has also been linked to an increased RNA transfer (tRNA) oxidation—which alters their own stability and function—and changes in individual tRNA species, that in turn may also act as a compensatory mechanism to cope with intrinsic and extrinsic stressors, including oxidative stress [3]. In this regard, a mass spectrometry analysis on the cerebellum of AD patients identified a reduction in specific tRNA synthetases [19]. In addition to dysfunctional ribosomes and translation impairments as early events in AD pathogenesis [3], these finding suggest that decreased levels of tRNA synthetases may lead to a decreased global protein synthesis, hampering pivotal mechanisms required for learning and memory setting in AD.

2. Ribosome Stalling and Ribosome-Associated Quality Control

A pivotal step of mRNA translation is elongation, in which ribosomes scan the mRNA sequence to gradually form the nascent polypeptide chain. This process plays a crucial role in different aspects of protein synthesis, including differential expression, secretion, covalent modification, and co-translational folding [20][21]. Ribosome stalling, a local accumulation of ribosomes at specific mRNA codon positions, is involved in several physiologic processes, including mRNA degradation [22], modification of protein conformations [23], and regulation of protein expression [24], but also in pathological conditions [25].
Pivotal components of the ribosome surveillance machinery are collectively called ribosome-associated quality control (RQC). When translational errors induced by stalling take place, the nascent peptidyl-tRNA chains—which are retained by the 60S subunit—recruit the RQC machinery for stalled ribosome resolution. The RQC complexes scan the arrested protein synthesis machinery to recycle stalled ribosomes by inducing the dissociation of 40S and 60S ribosomal subunits, and degrade abnormal mRNAs and polypeptides [26]. Mechanistically, listerin E3 ubiquitin protein ligase 1 (LTN1) targets the polypeptide chain produced during ribosome stalling for its proteolytic cleavage, while the ankyrin repeat and zinc finger peptidyl tRNA hydrolase 1 (ANKZF1) hydrolyses the tRNA from the ubiquitylated nascent chain before its degradation [26][27][28]. Nuclear export mediator factor (NEMF) modifies the nascent polypeptide chains produced by nonstop mRNAs—major erroneous mRNAs in mammals—with a C-terminal tail mainly composed of alanine (CAT-tail) to assist their ubiquitination and promote their degradation [29]. In addition, the functionally redundant E3 ubiquitin ligases cullin-RING E3 ubiquitin ligase 2 with its adaptor KLHDC10 (collectively indicated as CRL2KLHDC10) and ring finger and CHY zinc finger domain containing 1 (RCHY1) target C-terminal degrons and are involved in a NEMF-mediated, LTN1-independent degradation of RQC substrates to signal proteolysis and resolve stalled ribosomes’ protein products [30].
Failure of RQC is correlated with the persistence of unresolved stalled ribosomes and the sequestration of chaperone proteins, which interfere with the PQC system ultimately leading to and promoting protein aggregation [31]. This essential role of RQC in the proteostasis regulation has been linked with the proteotoxic effect of incomplete polypeptides produced by stalled ribosomes. Failure to degrade these aberrant nascent chains has been observed to be involved in mouse models of neurodegeneration [26][31][32]. Alterations in recycling stalled ribosomes in neurons have been linked to neurodegeneration, but the specific molecular mechanisms and signaling pathways triggered in response to ribosome stalling have yet to be completely elucidated. Recent evidence indicated that an inefficient RQC of ribosome stalling could be linked to the manifestations of AD hallmarks [33]. In AD mouse models and AD patients’ samples, during APP C-terminal fragment (APP.C99) co-translational translocation at the endoplasmic reticulum (ER) membrane, ribosomes stalled and activated the RQC machinery to resolve paused translation and ribosome collision. In case of inadequate RQC, aggregation-prone CAT-tailed APP.C99 induced autophagy and endolysosomal impairments, favoring the aggregation of Aβ peptides. These observations, together with the presence of RQC components at the Aβ plaque core, suggest a role of defective RQC of ribosome collision and stalled translation in AD pathogenesis [33]. Although RQC is a newly discovered mechanism, mutations in RQC components, such as LTN1 and NEMF have been shown to cause neurodegeneration [25][32] and a progressive development of motor neuron degeneration in ALS mice models [28]. In addition to impairment of central components of the elongation machinery, dysfunctional tRNAs have been observed to induce ribosome stalling, resulting in neurodegeneration. Alterations of tRNA levels due to genetic mutations can affect translation by impairing the elongation process. A single nucleotide mutation of n-Tr20—a brain-enriched arginine tRNA isoacceptor—in C57BL/6J mice models resulted in a severe impairment in tRNA processing and a reduction in its mature levels. These alterations led to a brain-specific increased ribosome occupancy at arginine AGA codons and abnormal ribosome stalling [25]. In addition, a n-Tr20 mutation associated with a mutation in GTP-binding protein 2 (GTPBP2)—a direct binding partner of pelota, a ribosome recycling protein—has been correlated with a significantly increased ribosome stalling at AGA codons, ataxia, and widespread neurodegeneration in the cerebellum, cortex, hippocampus, and retina areas [25]. Due to its homology to no-go/non-stop mRNA decay protein HSP70 subfamily B suppressor 1-like (HBS1L) and its interaction with pelota, GTPBP2 may play a pivotal role in rescuing and recycling stalled ribosomes. Here, GTPBP2 and pelota cooperate in in the resolution and recycling of paused ribosomes and the degradation of mRNA and nascent protein. While GTPBP2 can compensate n-Tr20 mutation-induced elongation defects, its absence exacerbates ribosome stalling, leading to neuronal death and neurodegeneration [34]. In addition, the GTPBP2 homologue GTPBP1 is involved in the same pathway. Its brain-specific loss during tRNA deficiency led to codon-specific ribosome pausing with consequent neurodegeneration [35]. Mutations in n-Tr20, GTPBP2, and GTPBP1, prior to neurodegeneration onset, were correlated with the following: (1) the activation of general control non-derepressible 2 kinase (GCN2, also known as eukaryotic translation initiation factor 2-alpha kinase 4, or EIF2AK4), resulting in increased eIF2α phosphorylation; (2) the upregulation of genes regulated by activating transcription factor 4 (ATF4), a pivotal transcription factor involved in the integrated stress response (ISR) pathway; (3) the decrease in mTORC1 signaling, ultimately leading to an increased stalled ribosome-correlated neuronal death [34][35]. This suggests the existence of a possible feedback loop between translation initiation, elongation defects, and ribosome stalling and of a pivotal crosstalk between RQC and PQC systems through the activation of surveillance pathways.
Increasing evidence suggests a potential involvement of ribosome stalling also in the development of other neurodegenerative diseases, such as FTD and ALS. Indeed, elongating polyribosomes have been shown to stall on GGGGCC (G4C2) repeat expansion in the C9orf72 gene, known to cause FTD and ALS (C9-ALS/FTD), leading to the production of neurodegeneration-driving dipeptide repeat proteins through repeat-associated non-AUG (RAN) translation and to translation inhibition [36]. In this regard, the RQC rate-limiting factor zinc finger protein 598, E3 ubiquitin ligase (ZNF598), has been shown to have a neuroprotective function in C9-ALS/FTD, since it co-translationally regulates the expression of C9orf72-derived protein to promote its degradation via the ubiquitin–proteasome pathway and to suppress proapoptotic caspase-3 activation, while ALS-linked mutant ZNF598R69C showed a loss of this function [37]. In addition, the cytoplasmic residency of the RBP fused in sarcoma (FUS, also known as translocated in sarcoma, TLS) is prevalent in ALS and FTD and could contribute to the translational stalling of polyribosomes in an RNA-binding dependent manner [38]. Upon different stress conditions, mTORC2 signal transduction is compromised, leading to a reduced translation via FUS recruitment. The FUS negatively regulates translation through its association with polyribosomes and RNA in response to mTORC2 inhibition, and its cytoplasmic retention increases its proximity to polyribosomes for stalling to occur. This localization to stalled polyribosomes exerts a toxic repression of mRNA translation, resulting in a decrease in global protein synthesis [38].
Taken together, these data suggest that defects in recycling stalled ribosomes in the neuron may participate in the development of neurodegeneration, although further investigations are necessary to unravel the precise mechanisms by which ribosome stalling leads to neuronal death. In this regard, recent advancements in the analysis of ribosomal footprints in endogenous mRNA transcripts may prompt important improvements for a better understanding of elongation dynamics and for identifying endogenous sources of ribosome pausing and stalling.

3. Protein Quality Control and Proteostasis Regulation

The maintenance of a functional and stable proteome through a tight regulation of protein folding homeostasis is vital for cell survival, and the cell has different quality control strategies to monitor and maintain the proteome integrity. Following translation, newly synthesized nascent polypeptides are constantly at risk of misfolding and aggregation. The PQC is an essential cellular mechanism involving a network of molecular chaperones and protein degradation pathways that ensures protein homeostasis by degrading misfolded proteins and aggregates in a timely fashion. Newly folded proteins transit through the ER–Golgi apparatus for their eventual post-translational modification and secretion. Chaperones facilitate folding of proteins or refolding misfolded proteins, while incorrectly folded proteins are recognized by ER-associated degradation (ERAD), then targeted through different mechanisms, including the ubiquitin (Ub)-proteasome system (UPS) [39][40], the autophagy-lysosome system [41][42] and chaperone-mediated autophagy (CMA) [43].
Due to its protein clearance activity, UPS plays a pivotal role in protein homeostasis during neurodegeneration by preventing protein misfolding and aggregation [4], and it regulates other several biological events, including transcription, DNA repair, cell cycle, and apoptosis [44]. In this context, molecular chaperones have a key role in proteostasis, as suggested by their protective role in the pathogenesis of neurodegenerative disorders in mouse models [45]. In this regard, they have been shown to inhibit the assembly of aggregation-prone proteins, such as Aβ and tau, and favor their UPS- or autophagy-mediated degradation [46]. In neurons, PQC and maintenance of proteostasis are demanding activities due to neuronal cellular structure and post-mitotic cellular state, which does not allow for the dilution of toxic substances through cell division. As a matter of fact, neurons are highly sensitive to misfolded proteins and their aggregates, and this susceptibility increases with their aging, as suggested by the correlation between PQC failure and neurodegenerative diseases [47][48]. Neurodegenerative pathologies, including AD, are characterized by misfolding and, consequently, abnormal aggregation of disease-causing or disease-developing proteins, such as Aβ and hyperphosphorylated tau. Production and accumulation of these protein aggregates—Aβ plaques in the extracellular milieu and tau neurofibrillary tangles in neurons—lead to an abnormal activation of cytoprotective mechanisms, including the unfolded protein response (UPR). The UPR is a complex mechanism associated with the ER and activated by three different molecular pathways involving inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also known as eukaryotic translation initiation factor 2-alpha kinase 3, EIF2AK3), and activating transcription factor 6 (ATF6). These signaling pathways lead to the transcriptional activation of UPR genes—including degradation proteins, redox enzymes, and several chaperones—and to eIF2α phosphorylation to suppress cap-dependent translation, ultimately resulting in SG formation. It is known that eIF2α can be phosphorylated by other kinases that collectively form the ISR, including PERK, PKR (also known as protein kinase RNA-activated, interferon-induced double stranded RNA-activated protein kinase or eukaryotic translation initiation factor 2-alpha kinase 2, EIF2AK2), GCN2, and heme-regulated eIF2α kinase (HRI, also known as eukaryotic translation initiation factor 1, EIF2AK1). The role of all four ISR kinases has been investigated in a neurodegeneration context, including AD. Their activation leads to a reduction in general translation and an increase in the expression of stress-related mRNAs, including β-secretase (BACE1) and ATF4. This accelerates the establishment of AD hallmarks, including tau phosphorylation, Aβ formation, and the induction of pro-apoptotic and autophagy pathways (reviewed in [49]). Furthermore, ISR kinases have been suggested to play important roles in AD development and progression for the following reasons: (1) PERK prolonged overactivation results in decreased protein synthesis, memory impairment, and neuronal loss, as well as in pathological tau phosphorylation and Aβ production [49]; (2) PKR is highly expressed and phosphorylated in AD brains, localized within and around neuritic and Aβ senile plaques and correlated with Aβ production and neurotoxicity-mediating neuroinflammation [50]; (3) GCN2 reduces global protein synthesis and upregulates stress-related mRNAs (e.g., ATF4 and BACE1), thus, accelerating Aβ production, tau phosphorylation, and neuronal apoptosis [49]; (4) HRI regulates BACE1 translation in glutamatergic hippocampal synapses, contributing to synaptogenesis and memory consolidation [49]. Therefore, these findings suggest an underlying dysregulation of the UPR and ISR mechanisms in neurodegenerative pathologies.
Indeed, although interrupting protein synthesis through these protective mechanisms can reduce cellular stress due to protein misfolding and aggregation, a persistent eIF2α-mediated arrest of global protein translation favors pathological SG formation, thus, negatively affecting neurons and interfering with the maintenance of their homeostasis and other neuronal functions. Defective ribosomal products (DRiPs) appear to be the most prominent species of misfolding proteins that accumulate inside SGs, and this correlate with the functionality of the PQC machinery and its players, which recognize damaged proteins and DRiPs and target them to the proteasome or autophagy, thus, maintaining the liquid-like properties of SGs, a process referred to as granulostasis, central for physiological SG behavior [51][52][53]. Impairments in PQC and SGs are major contributors in ALS/FTD pathogenesis, since mechanisms of protein folding and clearance are often dysfunctional in these pathologies [54]. Although mutations in different genes coding for proteins involved in UPS (that degrades soluble proteins with a short half-life) and autophagy (that degrades long-lived, misfolded, and aggregated proteins, as well as damaged organelles) [55] have been identified, mechanisms triggering aberrant SGs have also been shown not only in ALS/FTD, but also in AD [56]. One mechanism is represented by the alteration of cell signaling after mTORC1 sequestration, and defects in SG disassembly have deleterious consequences for cell viability by impairing protein synthesis and metabolic pathways, while sensitizing cells to apoptotic stimuli. When chaperone-mediated granulostasis fails to dissolve aberrant SGs, AN1-type zinc finger protein (ZFAND), the autophagy receptor SQSTM1/p62 and valosin-containing protein (VCP) can cooperate to degrade SGs via proteasome and autophagy, respectively. However, ALS/FTD mutations, such as in VCP, result in the accumulation of damaged proteins that, in turn, may indirectly favor their co-aggregation with SGs. Another mechanism through which SGs affect cell health is through sequestration of RBPs, that continuously shuttle between the nucleus and the cytoplasm to assist RNA transport and processing. Once in the cytoplasm, these RBPs show increased aggregation propensity, and this may enhance their sequestration inside SGs, promoting their conversion into an aberrant state. In ALS/FTD, TDP-43 and FUS mislocalization to the cytoplasm and their association to SGs represent a hallmark of these pathologies [57]. In addition, recent evidence reports that through a mechanism mediated by the RBP protein TIA1 and pathological SGs, oligomeric tau propagates toxic tau pathology, suggesting a broad role for SGs in the mechanisms of tau-mediated neurodegeneration [58][59]. Moreover, oTau pathology co-localizes with HNRNPA2B1 [17] and with other RPBs including PABP, HNRNPA0, eIF3η, and EWSR1 that are involved in tau-mediated neurodegeneration [56]. Indeed, during stress, an increased interaction between tau and mRNA is detectable in the somatodendritic arbour. The interaction of tau with SGs stimulates the formation of insoluble tau aggregates and has important consequences for the pathophysiology of tauopathies. These findings indicate that the physiology and pathophysiology of tau provide the biological link between RBPs and both SGs and the translational stress response [56].
Altogether, these considerations indicate that defects in UPS, autophagy, and vesicular transport contribute to ALS/FTD and AD pathogenesis, which is associated with the aggregation of misfolded proteins and the RBPs. In this regard, mutations and dysregulation of different RBP recruited into SGs can be either the primary cause or major contributors of neurodegenerative diseases [57]. Indeed, both genetic and experimental data reported a strong association between SG-recruited RBP protein aggregation and age-related pathologies.

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