Editing Stress granules

[[Key concepts in ALS]]

*[https://en.wikipedia.org/wiki/Stress_granule Wikipedia page]

Wikipedia: ''Stress granules are dense aggregations in the cytosol composed of proteins & RNAs that appear when the cell is under stress. {{#pmid:25736060|Gutierrez2015}} The RNA molecules stored are stalled translation pre-initiation complexes: failed attempts to make protein from mRNA. Stress granules are 100–200 nm in size, not surrounded by membrane, and associated with the endoplasmatic reticulum. {{#pmid:16055272|Kavali2005}}''

[[File:Fig-1-Stress-granule-assembly-and-interference-by-viruses-Virus-infection-causes.png|400px]]
[[File:nrm2694-f1.jpg|400px]]


== Specific for ALS ==

''Of note, both ALS and FTD are characterized by pathological inclusions, where some well-known SG markers localize with the ALS related proteins TDP-43 and FUS. '''We propose that TDP-43 and FUS serve as an interface between genetic susceptibility and environmental stress exposure in disease pathogenesis.''' Here, we will discuss the role of TDP-43 and FUS in SG dynamics and how disease-linked mutations affect this process.'' {{#pmid:26557057|Aulas2015}}

''Amyotrophic lateral sclerosis (ALS) is a fatal human neurodegenerative disease affecting primarily motor neurons. Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. '''TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. This property is critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis. Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis.''''' {{#pmid:23629963|Li2013}}

''Interest in RNA dysfunction in amyotrophic lateral sclerosis (ALS) recently aroused upon discovering causative mutations in RNA-binding protein genes. '''Here, we show that extensive down-regulation of miRNA levels is a common molecular denominator for multiple forms of human ALS. We further demonstrate that pathogenic ALS-causing mutations are sufficient to inhibit miRNA biogenesis at the Dicing step.''' Abnormalities of the stress response are involved in the pathogenesis of neurodegeneration, including ALS. Accordingly, we describe a novel mechanism for modulating microRNA biogenesis under stress, involving stress granule formation and re-organization of DICER and AGO2 protein interactions with their partners. In line with this observation, enhancing DICER activity by a small molecule, enoxacin, is beneficial for neuromuscular function in two independent ALS mouse models. Characterizing miRNA biogenesis downstream of the stress response ties seemingly disparate pathways in neurodegeneration and further suggests that DICER and miRNAs affect neuronal integrity and are possible therapeutic targets.'' {{#pmid:26330466|Emde2015}}

''Nuclear clearance of TDP-43 into cytoplasmic aggregates is a key driver of neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but the mechanisms are unclear. Here, we show that TDP-43 knockdown specifically reduces the number and motility of RAB11-positive recycling endosomes in dendrites, while TDP-43 overexpression has the opposite effect. This is associated with delayed transferrin recycling in TDP-43-knockdown neurons and decreased β2-transferrin levels in patient CSF Whole proteome quantification identified the upregulation of the ESCRT component VPS4B upon TDP-43 knockdown in neurons. Luciferase reporter assays and chromatin immunoprecipitation suggest that TDP-43 represses VPS4B transcription. Preventing VPS4B upregulation or expression of its functional antagonist ALIX restores trafficking of recycling endosomes. Proteomic analysis revealed the broad reduction in surface expression of key receptors upon TDP-43 knockdown, including ErbB4, the neuregulin 1 receptor. TDP-43 knockdown delays the surface delivery of ErbB4. ErbB4 overexpression, but not neuregulin 1 stimulation, prevents dendrite loss upon TDP-43 knockdown. Thus, impaired recycling of ErbB4 and other receptors to the cell surface may contribute to TDP-43-induced neurodegeneration by blocking trophic signaling.'' {{#pmid:27621269|Schwenk2016}}

'''''BACKGROUND:'''
Amyotrophic lateral sclerosis (ALS) shows a strong genetic basis, with SOD1, FUS, TARDBP, and C9ORF72 being the genes most frequently involved. This has allowed identification of asymptomatic mutation carriers, which may be of help in understanding the molecular changes preceding disease onset.
'''OBJECTIVES:'''
We studied the cellular expression of FUS protein and the effect of heat-shock- and dithiothreitol-induced stress in fibroblasts from FUS P525L mutation carriers, healthy controls, and patients with sporadic ALS.
'''METHODS:'''
Western blots and immunocytochemistry were performed to study the subcellular localization of FUS protein. Control and stressed cells were double stained with FUS and the stress marker TIA-R.
'''RESULTS:'''
Fibroblasts from healthy controls and sporadic ALS cases showed a prominent nuclear FUS expression. In the 2 FUS P525L mutation carriers, instead, most cells showed a protein localization in both nucleus and cytoplasm, or exclusively in the cytoplasm. Stress prompted the formation of cytoplasmic granules in all subjects and in sporadic ALS FUS mislocalization to the cytoplasm. Cytoplasmic FUS was recruited into stress granules, which showed a time-dependent decrease in all subjects. However, in the FUS P525L fibroblasts, the granules persisted longer, and they were more numerous than those detected in the cells from controls and sporadic ALS patients.
'''CONCLUSIONS:'''
We show that in fibroblasts of FUS P525L mutation carriers, FUS mislocalized to the cytoplasm where it redistributed into stress granules with likely a dose effect, i.e. a higher number of cells with granules, which persist longer, than in controls and ALS cases. These data represent an early molecular change occurring before ALS onset, suggesting a transient preaggregative state.'' {{#pmid:29035885|lobello2017}}

''Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 10-6). Postmortem neuropathology of five TIA1 mutations carriers showed a consistent pathological signature with numerous round, hyaline, TAR DNA-binding protein 43 (TDP-43)-positive inclusions. TIA1 mutations significantly increased the propensity of TIA1 protein to undergo phase transition. In live cells, TIA1 mutations delayed stress granule (SG) disassembly and promoted the accumulation of non-dynamic SGs that harbored TDP-43. Moreover, TDP-43 in SGs became less mobile and insoluble. The identification of TIA1 mutations in ALS/FTD reinforces the importance of RNA metabolism and SG dynamics in ALS/FTD pathogenesis.'' {{#pmid:28817800|mckenzie2017}}

== Formation ==

''Stress granules are non-membrane bound RNA-protein (RNP) assemblies that form when translation initiation is limited and contain a biphasic structure with stable core structures surrounded by a less concentrated shell. The order of assembly and disassembly of these two structures remains unknown. Time course analysis of granule assembly suggests that core formation is an early event in granule assembly. Stress granule disassembly is also a stepwise process with shell dissipation followed by core clearance. Perturbations that alter liquid-liquid phase separations (LLPS) driven by intrinsically disordered protein regions (IDR) of RNA binding proteins in vitro have the opposite effect on stress granule assembly in vivo. Taken together, these observations argue that '''stress granules assemble through a multistep process initiated by stable assembly of untranslated mRNPs into core structures, which could provide sufficient high local concentrations to allow for a localized LLPS driven by IDRs on RNA binding proteins.''''' {{#pmid:27602576|Wheeler2016}}

''TIA-1 is an RNA binding protein that promotes the assembly of stress granules (SGs), discrete cytoplasmic inclusions into which stalled translation initiation complexes are dynamically recruited in cells subjected to environmental stress. The RNA recognition motifs of TIA-1 are linked to a glutamine-rich prion-related domain (PRD). Truncation mutants lacking the PRD domain do not induce spontaneous SGs and are not recruited to arsenite-induced SGs, whereas the PRD forms aggregates that are recruited to SGs in low-level-expressing cells but prevent SG assembly in high-level-expressing cells. The PRD of TIA-1 exhibits many characteristics of prions: concentration-dependent aggregation that is inhibited by the molecular chaperone heat shock protein (HSP)70; resistance to protease digestion; sequestration of HSP27, HSP40, and HSP70; and induction of HSP70, a feedback regulator of PRD disaggregation. Substitution of the PRD with the aggregation domain of a yeast prion, SUP35-NM, reconstitutes SG assembly, confirming that a prion domain can mediate the assembly of SGs. Mouse embryomic fibroblasts (MEFs) lacking TIA-1 exhibit impaired ability to form SGs, although they exhibit normal phosphorylation of eukaryotic initiation factor (eIF)2alpha in response to arsenite. '''Our results reveal that prion-like aggregation of TIA-1 regulates SG formation downstream of eIF2alpha phosphorylation in response to stress.''''' {{#pmid:15371533|Gilks2004}} 

''Stress granules (SGs) are evolutionarily conserved ribonucleoprotein (RNP) structures that form in response to a variety of environmental and cellular cues. The presence of these RNP granules has been linked to a number of human diseases, including neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (Li et al., J Cell Biol 201:361-372, 2013; Nonhoff et al., Mol Biol Cell 18:1385-1396, 2007). Understanding how the assembly of these granules is controlled could, therefore, suggest possible routes of therapy for patients afflicted with these conditions. '''Interestingly, several reports have identified a potential role for protein deubiquitination in the assembly of these RNP granules. In particular, recent work has found that a specific deubiquitinase enzyme, Ubp3, is required for efficient SG formation in S. cerevisiae (Nostramo et al., Mol Cell Biol 36:173-183, 2016). This same enzyme has been linked to SGs in other organisms, including humans''' and the fission yeast, Schizosaccharomyces pombe (Takahashi et al., Mol Cell Biol 33:815-829, 2013; Wang et al., RNA 18:694-703, 2012). At first glance, these observations suggest that a striking degree of conservation exists for a ubiquitin-based mechanism controlling SG assembly. However, the devil is truly in the details here, as the precise nature of the involvement of this deubiquitinating enzyme seems to vary in each organism. Here, we briefly review these differences and attempt to provide an overarching model for the role of ubiquitin in SG formation.'' {{#pmid:26852120|Nostramo2016}}

''Amyotrophic lateral sclerosis is characterized by progressive loss of motor neurons in the brain and spinal cord. Mutations in several genes, including FUS, TDP43, Matrin 3, hnRNPA2 and other RNA-binding proteins, have been linked to ALS pathology. Recently, Pur-alpha, a DNA/RNA-binding protein was found to bind to C9orf72 repeat expansions and could possibly play a role in the pathogenesis of ALS. When overexpressed, Pur-alpha mitigates toxicities associated with Fragile X tumor ataxia syndrome (FXTAS) and C9orf72 repeat expansion diseases in Drosophila and mammalian cell culture models. However, the function of Pur-alpha in regulating ALS pathogenesis has not been fully understood. '''We identified Pur-alpha as a novel component of cytoplasmic stress granules (SGs) in ALS patient cells carrying disease-causing mutations in FUS. When cells were challenged with stress, we observed that Pur-alpha co-localized with mutant FUS in ALS patient cells and became trapped in constitutive SGs. We also found that FUS physically interacted with Pur-alpha in mammalian neuronal cells.''' Interestingly, shRNA-mediated knock down of endogenous Pur-alpha significantly reduced formation of cytoplasmic stress granules in mammalian cells suggesting that Pur-alpha is essential for the formation of SGs. Furthermore, ectopic expression of Pur-alpha blocked cytoplasmic mislocalization of mutant FUS and strongly suppressed toxicity associated with mutant FUS expression in primary motor neurons. Our data emphasizes the importance of stress granules in ALS pathogenesis and identifies Pur-alpha as a novel regulator of SG dynamics.'' {{#pmid:26728149|Daigle2016}}

== Formation anomalies in ALS ==

''The protein aggregation that occurs in neurodegenerative diseases is classically thought to occur as an undesirable, nonfunctional byproduct of protein misfolding. This model contrasts with the biology of RNA binding proteins, many of which are linked to neurodegenerative diseases. RNA binding proteins use protein aggregation as part of a normal regulated, physiological mechanism controlling protein synthesis. The process of regulated protein aggregation is most evident in formation of stress granules. Stress granules assemble when RNA binding proteins aggregate through their glycine rich domains. Stress granules function to sequester, silence and/or degrade RNA transcripts as part of a mechanism that adapts patterns of local RNA translation to facilitate the stress response. Aggregation of RNA binding proteins is reversible and is tightly regulated through pathways, such as phosphorylation of elongation initiation factor 2α. Microtubule associated protein tau also appears to regulate stress granule formation. Conversely, stress granule formation stimulates pathological changes associated with tau. In this review, '''I propose that the aggregation of many pathological, intracellular proteins, including TDP-43, FUS or tau, proceeds through the stress granule pathway.''' Mutations in genes coding for stress granule associated proteins or prolonged physiological stress, lead to enhanced stress granule formation, which accelerates the pathophysiology of protein aggregation in neurodegenerative diseases. Over-active stress granule formation could act to sequester functional RNA binding proteins and/or interfere with mRNA transport and translation, each of which might potentiate neurodegeneration. The reversibility of the stress granule pathway also offers novel opportunities to stimulate endogenous biochemical pathways to disaggregate these pathological stress granules, and perhaps delay the progression of disease.'' {{#pmid:23164372|Wolozin2012}} 

''Recent advances in neurodegenerative diseases point to novel mechanisms of protein aggregation. RNA binding proteins are abundant in the nucleus, where they carry out processes such as RNA splicing. Neurons also express RNA binding proteins in the cytoplasm and processes to enable functions such as mRNA transport and local protein synthesis. The biology of RNA binding proteins turns out to have important features that appear to promote the pathophysiology of amyotrophic lateral sclerosis and might contribute to other neurodegenerative disease. RNA binding proteins consolidate transcripts to form complexes, termed RNA granules, through a process of physiological aggregation mediated by glycine rich domains that exhibit low protein complexity and in some cases share homology to similar domains in known prion proteins. Under conditions of cell stress these RNA granules expand, leading to form stress granules, which function in part to sequester specialized transcript and promote translation of protective proteins. Studies in humans show that pathological aggregates occurring in ALS, Alzheimer's disease, and other dementias co-localize with stress granules. One increasingly appealing hypothesis is that mutations in RNA binding proteins or prolonged periods of stress cause formation of very stable, pathological stress granules. The consolidation of RNA binding proteins away from the nucleus and neuronal arbors into pathological stress granules might impair the normal physiological activities of these RNA binding proteins causing the neurodegeneration associated with these diseases. Conversely, therapeutic strategies focusing on reducing formation of pathological stress granules might be neuroprotective.'' {{#pmid:24411700|Wolozin2014}}

''Hexanucleotide repeat expansions in the C9ORF72 gene are causally associated with frontotemporal lobar dementia (FTLD) and/or amyotrophic lateral sclerosis (ALS). The physiological function of the normal C9ORF72 protein remains unclear. In this study, we characterized the subcellular localization of C9ORF72 to processing bodies (P-bodies) and its recruitment to stress granules (SGs) upon stress-related stimuli. Gain of function and loss of function experiments revealed that '''the long isoform of C9ORF72 protein regulates SG assembly. CRISPR/Cas9-mediated knockdown of C9ORF72 completely abolished SG formation, negatively impacted the expression of SG-associated proteins such as TIA-1 and HuR, and accelerated cell death.''' Loss of C9ORF72 expression further compromised cellular recovery responses after the removal of stress. Additionally, '''mimicking the pathogenic condition via the expression of hexanucleotide expansion upstream of C9ORF72 impaired the expression of the C9ORF72 protein, caused an abnormal accumulation of RNA foci, and led to the spontaneous formation of SGs.''' Our study identifies a novel function for normal C9ORF72 in SG assembly and sheds light into how the mutant expansions might impair SG formation and cellular-stress-related adaptive responses.'' {{#pmid:27037575|Maharjan2016}}

''Stress granules (SGs) are ribonucleoprotein complexes induced by stress. They sequester mRNAs and disassemble when the stress subsides, allowing translation restoration. '''In amyotrophic lateral sclerosis (ALS), aberrant SGs cannot disassemble and therefore accumulate and are degraded by autophagy.''' However, the molecular events causing aberrant SG formation and the molecular players regulating this transition are largely unknown. We report that defective ribosomal products (DRiPs) accumulate in SGs and promote a transition into an aberrant state that renders SGs resistant to RNase. We show that only a minor fraction of aberrant SGs is targeted by autophagy, whereas the majority disassembles in a process that requires assistance by the HSPB8-BAG3-HSP70 chaperone complex. We further demonstrate that HSPB8-BAG3-HSP70 ensures the functionality of SGs and restores proteostasis by targeting DRiPs for degradation. We propose a system of chaperone-mediated SG surveillance, or granulostasis, which regulates SG composition and dynamics and thus may play an important role in ALS.'' {{#pmid:27570075|Ganassi2016}}

''Here we have used translating ribosome affinity purification coupled with microarray analysis to identify the mRNAs being actively translated in motor neurons of mutant TDP-43(A315T) mice compared to age-matched non-transgenic littermates. No significant changes were found at 5 months (presymptomatic) of age, but at 10 months (symptomatic) the translational profile revealed significant changes in genes involved in RNA metabolic process, immune response and cell cycle regulation. Of 28 differentially expressed genes, seven had a ≥ 2-fold change; four were validated by immunofluorescence labelling of motor neurons in TDP-43(A315T) mice, and two of these were confirmed by immunohistochemistry in amyotrophic lateral sclerosis cases. '''Both of these identified genes, DDX58 and MTHFSD, are RNA-binding proteins, and we show that TDP-43 binds to their respective mRNAs and we identify MTHFSD as a novel component of stress granules.''' This discovery-based approach has for the first time revealed translational changes in motor neurons of a TDP-43 mouse model, identifying DDX58 and MTHFSD as two TDP-43 targets that are misregulated in amyotrophic lateral sclerosis.'' {{#pmid:26525917|MacNair2016}}

== Breaking up ==

''RNA dysregulation is a newly recognized disease mechanism in amyotrophic lateral sclerosis (ALS). Here we identify Drosophila fragile X mental retardation protein (dFMRP) as a robust genetic modifier of TDP-43-dependent toxicity in a Drosophila model of ALS. We find that dFMRP overexpression (dFMRP OE) mitigates TDP-43 dependent locomotor defects and reduced lifespan in Drosophila. TDP-43 and FMRP form a complex in flies and human cells. In motor neurons, TDP-43 expression increases the association of dFMRP with stress granules and colocalizes with polyA binding protein in a variant-dependent manner. '''Furthermore, dFMRP dosage modulates TDP-43 solubility and molecular mobility with overexpression of dFMRP resulting in a significant reduction of TDP-43 in the aggregate fraction.''' Polysome fractionation experiments indicate that dFMRP OE also relieves the translation inhibition of futsch mRNA, a TDP-43 target mRNA, which regulates neuromuscular synapse architecture. Restoration of futsch translation by dFMRP OE mitigates Futsch-dependent morphological phenotypes at the neuromuscular junction including synaptic size and presence of satellite boutons. Our data suggest a model whereby dFMRP is neuroprotective by remodeling TDP-43 containing RNA granules, reducing aggregation and restoring the translation of specific mRNAs in motor neurons.'' {{#pmid:26385636|Coyne2015}}

''DNA-binding protein 43 (TDP-43) is a major disease protein in amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases. Both the cytoplasmic accumulation of toxic ubiquitinated and hyperphosphorylated TDP-43 fragments and the loss of normal TDP-43 from the nucleus may contribute to the disease progression by impairing normal RNA and protein homeostasis. Therefore, both the removal of pathological protein and the rescue of TDP-43 mislocalization may be critical for halting or reversing TDP-43 proteinopathies. Here, we report poly(A)-binding protein nuclear 1 (PABPN1) as a novel TDP-43 interaction partner that acts as a potent suppressor of TDP-43 toxicity. '''Overexpression of full-length PABPN1 but not a truncated version lacking the nuclear localization signal protects from pathogenic TDP-43-mediated toxicity, promotes the degradation of pathological TDP-43 and restores normal solubility and nuclear localization of endogenous TDP-43.''' Reduced levels of PABPN1 enhances the phenotypes in several cell culture and Drosophila models of ALS and results in the cytoplasmic mislocalization of TDP-43. Moreover, PABPN1 rescues the dysregulated stress granule (SG) dynamics and facilitates the removal of persistent SGs in TDP-43-mediated disease conditions. These findings demonstrate a role for PABPN1 in rescuing several cytopathological features of TDP-43 proteinopathy by increasing the turnover of pathologic proteins.'' {{#pmid:26130692|Chou2015}}

''Certainly, small molecule activators of the UPS or autophagy have been shown to promote TDP-43 clearance and/or mitigate toxicity in models based on TDP-43 overexpression [66, 77, 98, 99]. Autophagy activators may offer selectivity in clearing misfolded TDP-43 [76, 79]; however, given the ability of TDP-43 to autoregulate, even nonselective clearance strategies hold promise for safely restoring TDP-43 proteostasis. [...] '''There are several intrinsic cellular mechanisms that can act to either prevent or resolve protein misfolding, namely the chaperone system, autophagy, and the UPS.''' The chaperone system maintains proper protein folding during synthesis and thereafter, or delivers misfolded substrates for degradation [161]. '''In the case of TDP-43, the chaperone heat shock protein (Hsp)90 enhances solubility (i.e., folding) [162], while [[HspB8]] promotes autophagic clearance of aggregated TDP-43 [163]. Potentiated forms of the disaggregase [[Hsp104]] can mediate TDP-43 refolding [161].''' Monomeric misfolded TDP-43 is likely handled by the UPS [76]'' {{#pmid:25652699|Scotter2015}}

''The aggregation of RNA-binding proteins is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). RBM45 is an RNA-binding protein that forms cytoplasmic inclusions in neurons and glia in ALS and FTLD. To explore the role of RBM45 in ALS and FTLD, we examined the contribution of the protein’s domains to its function, subcellular localization, and interaction with itself and ALS-linked proteins. '''We find that RBM45 forms homo-oligomers and physically associates with the ALS-linked proteins TDP-43 and FUS in the nucleus. Nuclear localization of RBM45 is mediated by a bipartite nuclear-localization sequence (NLS) located at the C-terminus. RBM45 mutants that lack a functional NLS accumulate in the cytoplasm and form TDP-43 positive stress granules. Moreover, we identify a novel structural element, termed the homo-oligomer assembly (HOA) domain, that is highly conserved across species and promote homo-oligomerization of RBM45.''' RBM45 mutants that fail to form homo-oligomers exhibit significantly reduced association with ALS-linked proteins and inclusion into stress granules. These results show that RMB45 may function as a homo-oligomer and that its oligomerization contributes to ALS/FTLD RNA-binding protein aggregation.'' {{#pmid:26391765|Yang2015}}

''TDP-43 pathology marks a spectrum of multisystem proteinopathies including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and sporadic inclusion body myositis. Surprisingly, it has been challenging to recapitulate this pathology, highlighting an incomplete understanding of TDP-43 regulatory mechanisms. Here we provide evidence supporting TDP-43 acetylation as a trigger for disease pathology. Using cultured cells and mouse skeletal muscle, we show that TDP-43 acetylation-mimics promote TDP-43 phosphorylation and ubiquitination, perturb mitochondria, and initiate degenerative inflammatory responses that resemble sporadic inclusion body myositis pathology. Analysis of functionally linked amyotrophic lateral sclerosis proteins revealed recruitment of p62, ubiquilin-2, and optineurin to TDP-43 aggregates. We demonstrate that TDP-43 acetylation-mimic pathology is potently suppressed by an HSF1-dependent mechanism that disaggregates TDP-43. Our study illustrates bidirectional TDP-43 processing in which TDP-43 aggregation is targeted by a coordinated chaperone response. Thus, activation or restoration of refolding mechanisms may alleviate TDP-43 aggregation in tissues that are uniquely susceptible to TDP-43 proteinopathies.TDP-43 aggregation is linked to various diseases including amyotrophic lateral sclerosis. '''Here the authors show that acetylation of the protein triggers TDP-43 pathology in cultured cells and mouse skeletal muscle, which can be cleared through an HSF1-dependent chaperone mechanism that disaggregates the protein.''''' {{#pmid:28724966|wang2017}}

== References ==

[[Category:Key concepts]]