
Citation: Atsushi Tsubota, Hidenori Ichijo, Kengo Homma. Mislocalization, aggregation formation and defect in proteolysis in ALS[J]. AIMS Molecular Science, 2016, 3(2): 246-268. doi: 10.3934/molsci.2016.2.246
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Asthma is a chronic respiratory disease characterized by inflammation of the respiratory tract, increased airway hypersensitivity, and reversible airway obstruction, affecting patients of all ages [1]. There are various types of patients, ranging from patients with mild symptoms to those whose treatment is difficult to control, and it affects their quality of life.
Although asthma can be controlled by standard therapy with a combination of inhaled corticosteroid and long-acting β2-stimulant (ICS/LABA) treatment, approximately 3–10% of asthma patients are estimated to suffer from severe asthma [2]–[4]. They account for more than 50% of all asthma medical expenses, and new treatments still need to be developed.
Generally, asthma was thought to be based on the involvement of Th2 cells and eosinophilic airway inflammation. However, recently, the presence of non-eosinophilic asthma, which is not associated with a predisposition to allergies and has little eosinophilic inflammation of the respiratory tract, has become prevalent.
To classify simply, asthma is divided into two main categories: type 2 asthma and non-type 2 asthma [5]. Recently, it has been classified by phenotype and endotype based on clinical features, laboratory findings, and genetic background [6]–[13]. For example, it is classified into allergic eosinophilic asthma, non-allergic eosinophilic asthma, and non-eosinophilic (neutrophilic) asthma.
When making a plan for treatment, it is easy to understand that the treatment method is determined by phenotype and endotype. Not only that, classified by phenotype and endotype seems easy to do research on future therapeutic drugs. Recent studies of severe asthma have shown that the patients are not atopic, and eosinophilia and Th2-cytokines are not characteristic in some cases. In severe asthma, the balance between type 2 inflammation and non-type 2 inflammation is assumed to be different.
In this review, we will summarize the therapeutic options for severe asthma and propose a phenotype-endotype-based treatment algorithm for patients with severe and difficult-to-treat asthma.
Cytokine-mediated immunity plays a dominant role in the pathogenesis of asthma.
Dendritic cells take up allergens, present antigens to Th0 (naïve T) cells, and differentiate into Th2 cells. IL-5 produced by Th2 cells is a strong eosinophil activator. IL-4 induces IgE production from B cells, and IL-13 is also involved in airway remodeling. In addition to Th2 cells, ILC2 (type 2 natural lymphocytes) cells are activated by IL-25 and IL-33 produced from epithelial tract cells after infection and allergen exposure. They also produce large amounts of IL-5 and IL-13. In short, IL-5 and IL-13 are secreted from both Th2 and ILC2 cells. Inflammation caused by Th2 and ILC2 cells is called type 2 inflammation (Figure 1).
On the other hand, the non-type 2 inflammatory reaction is assumed to involve IL-17 that acts on airway epithelial cells, which induces the production of IL-8 and G-CSF, which induce neutrophil migration and activation. IL-17 has been reported to correlate with neutrophil count and asthma severity [14].
In addition to type 2 therapeutics, non-type 2 inflammation, which is similar to chronic obstructive pulmonary disease (COPD), is also being investigated. At present, biologics targeting type 2 inflammation have been developed and approved, but no biologics targeting non-type 2 inflammation are currently available. Thus, macrolides and bronchial thermoplasty are options for additional treatment of non-type 2 inflammatory asthma.
The definition of severe asthma has changed in recent years. Recent GINA/NAEPP guidelines define asthma severity based on the level of treatment used to maintain adequate asthma control [1],[15],[16].
Difficult-to-treat asthma is asthma that is difficult to control, even with high-dose ICS treatment and other multiple asthma medications.
Severe asthma is one of the difficult-to-treat asthmas, which is difficult to control even when a leukotriene receptor antagonist or theophylline is used in addition to high-dose ICS/LABA treatment, or systemic glucocorticoid treatment is needed.
Recent studies have reported that blocking IgE, IL-5, IL-4, IL-13, IL-9, TSLP, and CCR3 may be effective in the treatment of allergic eosinophilic asthma [17]–[24].
Novel therapeutic strategies with type 2 inflammation-targeted biologics have been developed for severe asthma, with omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab having been approved worldwide.
This section mainly describes currently approved anti-IgE, anti-IL-5, and IL-4 agents.
Patients with allergic diseases have elevated serum IgE levels that induce rapid release of bioactive substances (degranulation reaction) stored in intracellular granules of mast cells and basophils. Thus, IgE is an important mediator of allergic reactions, like histamine.
Omalizumab is the first recombinant humanized IgG1 monoclonal antibody; it binds to free IgE, interrupting the IgE-mediated asthma inflammatory cascade at an early stage. Omalizumab was the earliest approved monoclonal antibody (mAb) therapy for asthma.
The purpose of its interrupting effect is to prevent mast cell activation and subsequent generation of its inflammatory mediators when IgE is activated by allergens. Thus, omalizumab reduces early- and late-phase asthmatic responses.
Randomized, controlled, clinical trials of omalizumab have been performed. Omalizumab significantly decreases asthma exacerbations and reduces the use of oral corticosteroids (OCSs), the amount of ICSs, and rescue use, and improves respiratory symptoms and quality of life [17],[25]–[27].
Omalizumab is usually administered subcutaneously. Although there are some differences in each country, the administration conditions are basically similar.
Patients' serum total IgE and body weight are measured before the first dose. Omalizumab is administered in addition to the standard defined when the concentration is calculated in terms of dose (when 30 IU/mL or more and 1500 IU/mL or less are satisfied).
Additionally, 16 weeks after the start of omalizumab, doctors comprehensively evaluate the effectiveness of treatment, and it should be continued only in patients who show marked improvements in their asthma.
Eosinophilic bronchial asthma is characterized by increased eosinophil counts in the airways and peripheral blood, which have been shown to positively correlate with asthma severity [28].
Interleukin 5 (IL-5) is a 13-amino acid protein that forms a 52-kDa homodimer binding to the IL-5 receptors on cell surfaces, a heterodimer composed of α and β subunits. The α subunit is specific for IL-5, and it is expressed on human eosinophil and basophil progenitors in bone marrow, as well as on mature circulating and tissue eosinophils and basophils.
The β subunit is responsible for cell signaling, shared with the granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3) receptors [29],[30]. It plays an important role in promoting growth, differentiation, and maturation of eosinophils in the bone marrow, along with their survival and activation in peripheral tissues.
Regarding the pathogenesis of bronchial asthma, IL-5α produced by type 2 helper T cells (Th2 cells) has been shown to play an important role in the pathogenesis of airway inflammation through proliferation and activation of eosinophils [31].
Thus, it was thought that asthma symptoms could be suppressed by an agent 1) if it binds to human IL-5 with high affinity (mepolizumab and reslizumab), or 2) if the binding of the ligand to the IL-5 receptor complex α-subunit could be inhibited (benralizumab). Both anti-IL-5 monoclonal antibodies (mAbs) (mepolizumab and reslizumab) and anti-IL-5Rα (benralizumab) have been shown to reduce circulating eosinophils and improve asthma control in patients with severe eosinophilic asthma, in particular in patients with elevated eosinophilic blood counts at baseline [32]. They are indicated for patients with a blood eosinophil count of 300 cells/µL or more and repeated acute exacerbations.
Mepolizumab was the first anti-IL-5 antibody; it binds to Il-5, inhibiting its interaction with its eosinophil surface receptor.
In 2000, a clinical study of mepolizumab was conducted [33], but because the subjects were not limited to patients with eosinophilic asthma, its effectiveness for asthma treatment was not proven. Later, a large-scale study focusing on eosinophilic asthma proved that it was effective [33].
Thus, when using mepolizumab, it is important to confirm the blood eosinophil count at ≥300 cells/µL.
Efficacy and safety in an international trial were confirmed in severe asthma patients (increased asthma exacerbations more than once in the past 12 months using high-dose ICS treatment and other therapeutic agents), including Japanese patients. Mepolizumab was approved in the USA and Europe in 2015.
Mepolizumab is usually administered subcutaneously at a dose of 100 mg every 4 weeks [34],[35] to patients whose blood eosinophil count was 300 cells/µL or more in the past 12 months.
In the combined analysis of SIRIUS [36] and MENSA [34], adverse events such as headache (19%), injection site reaction (8%), back pain (5%), and malaise (5%) were observed, but there were no cases of anaphylaxis or death. In the long-term COSMOS study [37], the side effect profile was similar.
Reslizumab is a high-affinity, humanized anti-interleukin (IL)-5 monoclonal (IgG4/κ) antibody. Reslizumab is also directed against IL-5, the same as mepolizumab, which inhibits activity within the IL-5 signaling pathway by reducing ligand-receptor interactions, and it reduces blood and tissue eosinophils in patients with asthma [38],[39].
Reslizumab has two features that are different from mepolizumab: it is used intravenously, and its dose depends on weight 3 mg/kg every 4 weeks. Reslizumab is usually administered intravenously at 3 mg/kg every 4 weeks to patients whose blood eosinophil count is ≥400 cells/µL, and it binds to IL-5 directly, the same as mepolizumab. Reslizumab is not currently approved for use in Japan.
The IL-5 receptor is a heterodimer of an α chain of the IL-5 receptor and a β chain receptor common to IL-3 and granulocyte macrophage colony-stimulating factor (GM-CSF) receptors. Benralizumab is a fully humanized afucosylated IgG1κ mAb that binds to an epitope on IL-5Rα. It inhibits IL-5 signaling, independently of ligand presence [40]. It also sustains antibody-directed cell-mediated cytotoxicity (ADCC) of eosinophils and basophils, leading to depletion of blood, tissue, and bone marrow eosinophilia [41]. Benralizumab is more likely to suppress eosinophilic inflammation than mepolizumab or reslizumab, because it is said that GM-CSF and IL-3 are related to the infiltration and activation of eosinophils in tissues. In clinical practice, it is highly likely that the target patient group will overlap with the anti-IL-5 antibody (mepolizumab, reslizumab) groups, and it is necessary to examine its proper use. The efficacy and safety of benralizumab for patients with severe asthma were confirmed by several studied [42],[43]. And, SK Mathur et al. showed an improvement of lung functions in asthmatic patients treated by benralizumab [44].
Benralizumab is usually administered subcutaneously at 30 mg every 4 weeks for the first 3 doses, and then every 8 weeks to patients whose blood eosinophil count is ≥300 cells/µL.
The Th2 cytokines IL-4 and IL-13 were discovered in the early 1980s, and they play a key role in the pathogenesis of allergic disorders. There are two types of IL-4 receptors, type 1 and type 2 [45]–[47]. The type 1 receptor is a heterodimer of IL-4Rα and a common γ-chain. When IL-4 binds to IL-4Rα, the γ-chain is recruited, and a signal is transmitted into the cell. IL-4Rα is expressed in various cells, but the γ-chain is expressed mainly in hematopoietic cells. Therefore, the type 1 receptor is expressed mainly in hematopoietic cells such as T cells and B cells. Type 2 receptors are composed of IL-4Rα and IL-13Rα1. The type 1 receptor transmits only IL-4 signals, whereas the type 2 receptor transmits both IL-4 and IL-13 signals. When IL-4 binds to IL-4Rα, IL-13Rα1 is recruited. On the other hand, when IL-13 binds to IL-13Rα1, IL-4Rα is recruited, and signals are transmitted. Type 2 receptors are expressed on some hematopoietic cells, but they are also expressed mainly on non-hematopoietic cells such as epithelial cells.
Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both IL-4 and IL-13 signaling, as mentioned above, because IL-4Rα is a common subunit of IL-13 and IL-4. In Japan, it was approved for atopic dermatitis prior to asthma and has been shown to be effective.
Recently, it also gained approval as add-on treatment for moderate-to-severe asthma in adolescents and adults. Phase II and III randomized, controlled trials demonstrated improvements in asthma exacerbation rates, FEV1, oral glucocorticoid use, and a range of patient-reported outcomes.
IL-4 has been shown to stimulate IgE production from B cells, and IL-13 expression correlates with disease severity and flares [48].
In short, IL-4 plays a major role in Th2 cell proliferation, IgE synthesis, and cytokine production. Additionally, IL-13 has a major role in the pathological features of disease (mucus production, airway hyperresponsiveness, and collagen deposition [49]. Regarding IL-13 regulation, it has been reported that inhibiting IL-4R is more effective than only an IL-13 antibody that controls bronchial asthma [50],[51]. Therefore, dupilumab is considered to be an effective treatment when patients have abundant airway secretions. The blood eosinophil count and exhaled nitric oxide concentration (FeNO) are effective biomarkers. The usefulness of FeNO in the therapeutic effect of dupilumab is characteristic, unlike anti-IL-5 drugs. Moreover, after therapy, serum total IgE, periostin, TARC, and eotaxin-3 have been shown to be decreased in humans. The number of blood eosinophils increases transiently after therapy and then returns to baseline. This may indicate that, in order to reduce production of eosinophil-directed chemokines in the local area of lung inflammation, blood eosinophils are not mobilized to the lung temporarily.
Dupilumab is usually administered subcutaneously and is approved for use in atopic dermatitis and asthma in adults. In cases of asthma, for adults and children 12 years of age and older, 600 mg of dupilumab is administered subcutaneously the first time, and then 300 mg is administered subcutaneously every two weeks. Side effects are similar to those of IL-5 antibodies, but eosinophilia is unique to dupilumab.
In addition to the Th2 cells and mast cells, IL-33 stimulates Group 2 innate lymphoid cells (ILC2s) to produce Th2 cytokines [52]. On the other hand, IL-33 stimulates Th2 cells together with antigen to enhance IL-5/IL-13 production, and it is also involved in the development and enhancement of acquired allergy. In other words, IL-33 appears to be an important regulator of both natural and acquired allergies [53]. IL-33 antibody are being tested in severe asthma.
Thymic stromal lymphopoietin (TSLP) promotes Th2 differentiation by dendritic cells. ILC2 cells produce a large amount of IL-5 and IL-13 and play an important role in allergic airway inflammation. TSLP induces steroid resistance of ILC2s and helps activate ILC2 [54]. TSLP secreted from respiratory epithelial cells by viral infection or allergen stimulation (i) acts on dendritic cells to promote Th2 differentiation, (ii) suppresses regulatory T cells (Tregs) that act on lymphocyte inhibition, and (iii) induces steroid resistance of ILC2s. When the effects were investigated, asthma exacerbation was found to be suppressed regardless of the number of eosinophils in the blood, and its effectiveness for neutrophilic asthma is of interest. In ongoing Phase III clinical studies, it is necessary to verify whether TSLP antibodies are actually effective in neutrophilic asthma.
Currently, ICS treatment is the first choice in global guidelines for bronchial asthma treatment.
Depending on the severity, long-acting β2 stimulants, leukotriene receptor antagonists, theophylline, long-acting anticholinergic drugs, oral steroids, etc. are used. However, there are difficult-to-treat asthma cases that develop exacerbations of asthma even after combination therapy with ICS and other drugs.
Recently, several biologics were examined and have been approved to target T2 airway inflammation in patients with severe asthma. Multiple biologics targeting T2-high asthma are effective in the appropriate groups of severe asthma.
Before using biologics, however, it is important to determine whether there are comorbidities that worsen asthma, or whether low-cost treatments such as LAMA and theophylline have been curative. It is also necessary to confirm adherence and consider the use of antibody drugs if any treatment other than biologics still provides poor results.
(1) Review of diagnosis
(2) Confirmation of disease complications other than asthma
(3) Confirmation of drug adherence
(4) Increased ICS doses or additional inexpensive treatments
(5) Categorize strategies by type 2 inflammation
(6) Consider molecular biological preparations if acute exacerbations are repeated even after treatment with type 2 inflammation with a high ICS dose and other inexpensive treatments.
(7) In the case of not type 2, the possibility that anti-TSLP and other biological drugs can be expected is considered, but at present, macrolide treatment and bronchial thermoplasty (BT) are used.
With regard to the use of molecular biologics, since there is overlap in what is applicable to some cases, treating physicians must select the appropriate drugs. Finally, the characteristics that will be helpful for selection are described.
(1) The oldest anti-IgE antibody (omalizumab) has been established for about 10 years and has shown long-term safety, and it may be possible to discontinue it after long-term use.
(2) Anti-IL-5 and anti-IL-5α antibodies decrease blood eosinophils, but not omalizumab, and dupilumab not only does not decrease eosinophils, but it also increases them temporarily.
(3) Eosinophil depletion ability is even stronger for IL-5α (benralizumab) than for other IL-5 antibodies.
(4) Anti-IgE antibodies are expected to have long-term effects predicted in a comprehensive assessment after 4 months, but the long-term effects of other molecular biologics are unpredictable at this time.Thus, there are reports that anti-IgE antibodies should be used first when indications overlap.
(5) Maintenance treatment with benralizumab is every 8 weeks, and the burden on patients is light. Dupilumab can be self-injected, but it is given every 2 weeks.
(6) Anti-IL-5 has been established to have long-term safety for about 5 years, but the long-term safety of IL-5α (benralizumab) and dupilumab has been shown for only a few years.
Bousquet et al. proposed that omalizumab should be considered first-line therapy due to its safety as assessed by a large body of real-life data and over a decade of post-marketing surveillance [55]. However, not all patients receiving omalizumab seemed to respond well to treatment. The issue is complicated by the fact that blood eosinophil counts are a selection criterion and a strong predictor of response to treatment with mepolizumab, as largely previous reported, while IgE levels guide treatment selection for the use of omalizumab but are not predictive of response to omalizumab. The EXTRA study has instead shown the potential of fractional exhaled nitric oxide (FeNO), the peripheral blood eosinophil count, and serum periostin as predictors of the treatment effects of omalizumab [56]. The benefit of omalizumab is probably greater in patients who have early-onset allergic asthma and in younger patients [57], whereas anti-IL 5 treatments are more suitable for patients with late-onset asthma.
Regarding anti-IL5 drugs, an indirect drug comparison recently showed that mepolizumab was more effective in reducing exacerbations and in controlling asthma in patients with an eosinophil count ≥400 cells/µL compared to benralizumab and reslizumab. The study also found that benralizumab was more effective in improving lung function than reslizumab in patients with an eosinophil count ≥400 cells/µL [58]. However, when baseline patient characteristics were matched across asthma trials, benralizumab and mepolizumab showed similar efficacy [59].
With respect to comorbidities, there have been some studies. For example, Carpagnano GE et al. suggested the efficacy of mepolizumab in terms of reduction of inflammation and increased control in severe eosinophilic asthma with bronchiectasis [60]. Additionally, Alexander et al. suggested the efficacy of anti-IL5 therapy (mepolizumab/reslizumab) and anti-IgE therapy (omalizumab) in nasal polyps with asthma [61].
In my opinion, when asthma is divided into (i) allergic eosinophilic asthma, (ii) non-allergic eosinophilic asthma, and (iii) non-eosinophilic asthma, in the case of (i), when IgE is in the range of 30–1500 IU/mL, first use omalizumab, and consider continuation or treatment change at the 4-month re-examination. If the effect is insufficient at the re-examination, select an anti-IL-5 or anti-IL-5α agent if the eosinophilia is over 500 cells/µL. If there are not many eosinophils, use dupilumab. If there is prominent atopic dermatitis, use dupilumab from the beginning. In the case of (ii), anti-IL-5 and anti-IL-5α agents are used. Anti-IL-5 antibody is used for EGPA, and anti-IL-5α antibody is used when eosinophilia affects other organs, such as eosinophilic sinusitis and eosinophilic myocarditis. In the case of (iii), there is no effective molecular target drug yet, so the approach becomes dependent on BT therapy, macrolides, and OCS treatment. If IgE in an asthmatic patient meets the amount for use of omalizumab, use omalizumab first and consider continuation or treatment change at the 4-month re-examination. Select dupilumab if there are prominent secretions. Individual patients have different characteristics, and it is dangerous to judge only by pheno-endotype.
Biologics are effective against severe-uncontrolled asthma, mainly Th2.
Anti-IL-5, anti-IL-4/13, and anti-IgE drugs have been confirmed and approved in large-scale phase III trials. There are other unapproved products, such as anti-IL-13 and TSLP, but the therapeutic agents for Th2-type asthma have evolved and are expected to be useful in the future. With the advent of molecular targeted drugs, stratified therapy based on the phenotype of asthma has begun (Figure 2). Stratified treatment is expected to become more comprehensive with drugs currently being developed and approved in the future.
Future topics include the identification of biomarkers for the treatment of asthma and the development of non-Th2 type therapeutics. In addition, it may be necessary to investigate the use of biologics for long periods of time. To assess the long-term effects including adverse events, asthma patients treated with biologics should be followed for long periods of time.
[1] |
Rosen DR, Siddique T, Patterson D, et al. (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362: 59-62. doi: 10.1038/362059a0
![]() |
[2] | Sreedharan J, Blair IP, Tripathi VB, et al. (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 249: 1668-1672. |
[3] |
DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72: 245-256. doi: 10.1016/j.neuron.2011.09.011
![]() |
[4] |
Renton AE, Majounie E, Waite A, et al. (2011) A Hexanucleotide repeat expansion in C9ORF72 is the aause of chromosome 9p21-linked ALS-FTD. Neuron 72: 257-268. doi: 10.1016/j.neuron.2011.09.010
![]() |
[5] |
Majounie E, Renton AE, Mok K, et al. (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 11: 323-330. doi: 10.1016/S1474-4422(12)70043-1
![]() |
[6] |
Keller BA, Volkening K, Droppelmann CA, et al. (2012) Co-aggregation of RNA binding proteins in ALS spinal motor neurons: evidence of a common pathogenic mechanism. Acta Neuropathol 124: 733-747. doi: 10.1007/s00401-012-1035-z
![]() |
[7] | Neumann M, Sampathu DM, Kwong LK, et al. (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 130: 130-133. |
[8] |
Arai T, Hasegawa M, Akiyama H, et al. (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351: 602-611. doi: 10.1016/j.bbrc.2006.10.093
![]() |
[9] |
Leigh PN, Anderton BH, Dodson A, et al. (1988) Ubiquitin deposits in anterior horn cells in motor neuron disease. Neurosci Lett 93: 197-203. doi: 10.1016/0304-3940(88)90081-X
![]() |
[10] |
Johnson JO, Mandrioli J, Benatar M, et al. (2010) Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68: 857-864. doi: 10.1016/j.neuron.2010.11.036
![]() |
[11] |
Deng H-X, Chen W, Hong S-T, et al. (2011) Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477: 211-215. doi: 10.1038/nature10353
![]() |
[12] |
Maruyama H, Morino H, Ito H, et al. (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465: 223-226. doi: 10.1038/nature08971
![]() |
[13] | ALSoD (Amyotrophic Lateral Sclerosis Online Genetics Database). Available from: http://alsod.iop.kcl.ac.uk/ |
[14] |
Cleveland DW, Laing N, Hurse PV, et al. (1995) Toxic mutants in Charcot’s sclerosis. Nature 378: 342-343. doi: 10.1038/378342a0
![]() |
[15] | Bruijn LI, Houseweart MK, Kato S, et al. (1998) Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science 281: 1851-1854. |
[16] |
Hayward LJ, Rodriguez JA, Kim JW, et al. (2002) Decreased metallation and activity in subsets of mutant superoxide dismutases associated with familial amyotrophic lateral sclerosis. J Biol Chem 277: 15923-15931. doi: 10.1074/jbc.M112087200
![]() |
[17] |
Reaume AG, Elliott JL, Hoffman EK, et al. (1996) Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet 13: 43-47. doi: 10.1038/ng0596-43
![]() |
[18] |
Fujisawa T, Homma K, Yamaguchi N, et al. (2012) A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants. Ann Neurol 72: 739-49. doi: 10.1002/ana.23668
![]() |
[19] |
Urushitani M, Ezzi SA, Julien JP (2007) Therapeutic effects of immunization with mutant superoxide dismutase in mice models of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 104: 2495-2500. doi: 10.1073/pnas.0606201104
![]() |
[20] |
Bosco DA, Morfini G, Karabacak NM, et al. (2010) Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat Neurosci 13: 1396-1403. doi: 10.1038/nn.2660
![]() |
[21] |
Watanabe M, Dykes-Hoberg M, Culotta VC, et al. (2001) Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Neurobiol Dis 8: 933-941. doi: 10.1006/nbdi.2001.0443
![]() |
[22] |
Basso M, Massignan T, Samengo G, et al. (2006) Insoluble mutant SOD1 is partly oligoubiquitinated in amyotrophic lateral sclerosis mice. J Biol Chem 281: 33325-33335. doi: 10.1074/jbc.M603489200
![]() |
[23] |
Wang J, Xu G, Gonzales V, et al. (2002) Fibrillar inclusions and motor neuron degeneration in transgenic mice expressing superoxide dismutase 1 with a disrupted copper-binding site. Neurobiol Dis 10: 128-138. doi: 10.1006/nbdi.2002.0498
![]() |
[24] |
Furukawa Y, Fu R, Deng HX, et al. (2006) Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice. Proc Natl Acad Sci U S A 103: 7148-7153. doi: 10.1073/pnas.0602048103
![]() |
[25] |
Rodriguez JA, Valentine JS, Eggers DK, et al. (2002) Familial amyotrophic lateral sclerosis-associated mutations decrease the thermal stability of distinctly metallated species of human Copper/Zinc superoxide dismutase. J Biol Chem 277: 15932-15937. doi: 10.1074/jbc.M112088200
![]() |
[26] |
Sea K, Sohn SH, Durazo A, et al. (2015) Insights into the role of the unusual disulfide bond in Copper-Zinc superoxide dismutase. J Biol Chem 290: 2405-2418. doi: 10.1074/jbc.M114.588798
![]() |
[27] |
Doucette PA, Whitson LJ, Cao X, et al. (2004) Dissociation of human copper-zinc superoxide dismutase dimers using chaotrope and reductant: Insights into the molecular basis for dimer stability. J Biol Chem 279: 54558-54566. doi: 10.1074/jbc.M409744200
![]() |
[28] |
Hough MA, Grossmann JG, Antonyuk SV, et al. (2004) Dimer destabilization in superoxide dismutase may result in disease-causing properties: structures of motor neuron disease mutants. Proc Natl Acad Sci U S A 101: 5976-5981. doi: 10.1073/pnas.0305143101
![]() |
[29] |
Araki K, Iemura S, Kamiya Y, et al. (2013) Ero1-α and PDIs constitute a hierarchical electron transfer network of endoplasmic reticulum oxidoreductases. J Cell Biol 202: 861-874. doi: 10.1083/jcb.201303027
![]() |
[30] |
Atkin JD, Farg MA, Turner BJ, et al. (2006) Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1. J Biol Chem 281: 30152-30165. doi: 10.1074/jbc.M603393200
![]() |
[31] |
Chen X, Zhang X, Li C, et al. (2013) S-nitrosylated protein disulfide isomerase contributes to mutant SOD1 aggregates in amyotrophic lateral sclerosis. J Neurochem 124: 45-58. doi: 10.1111/jnc.12046
![]() |
[32] |
Jeon GS, Nakamura T, Lee JS, et al. (2014) Potential effect of S-nitrosylated protein disulfide isomerase on mutant SOD1 aggregation and neuronal cell death in amyotrophic lateral sclerosis. Mol Neurobiol 49: 796-807. doi: 10.1007/s12035-013-8562-z
![]() |
[33] | Honjo Y, Kaneko S, Ito H, et al. (2011) Protein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2968: 1-7. |
[34] |
Toichi K, Yamanaka K, Furukawa Y (2013) Disulfide scrambling describes the oligomer formation of superoxide dismutase (SOD1) proteins in the familial form of amyotrophic lateral sclerosis. J Biol Chem 288: 4970-4980. doi: 10.1074/jbc.M112.414235
![]() |
[35] | Crow JP, Sampson JB, Zhuang Y, et al. (1997) Decreased zinc affinity of amyotrophic lateral sclerosis-associated superoxide dismutase mutants leads to enhanced catalysis of tyrosine nitration by peroxynitrite. J Neurochem 69: 1936-1944. |
[36] |
Lyons TJ, Liu H, Goto JJ, et al. (1996) Mutation in copper-zinc superoxide dismutase that cause amyotrophic lateral sclerosis alter the zinc binding site and the redox behavior of the protein. Proc Natl Acad Sci U S A 93: 12240-12244. doi: 10.1073/pnas.93.22.12240
![]() |
[37] |
Homma K, Fujisawa T, Tsuburaya N, et al. (2013) SOD1 as a molecular switch for initiating the homeostatic ER stress response under zinc deficiency. Mol Cell 52: 75-86. doi: 10.1016/j.molcel.2013.08.038
![]() |
[38] |
Urushitani M, Sik A, Sakurai T, et al. (2006) Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nat Neurosci 9: 108-118. doi: 10.1038/nn1603
![]() |
[39] |
Israelson A, Ditsworth D, Sun S, et al. (2013) Macrophage migration inhibitory factor as a chaperone inhibiting accumulation of misfolded SOD1. Neuron 86: 218–232. doi: 10.1016/j.neuron.2015.02.034
![]() |
[40] |
Tan W, Naniche N, Bogush A, et al. (2013) Small peptides against the mutant SOD1/Bcl-2 toxic mitochondrial complex restore mitochondrial function and cell viability in mutant SOD1-mediated ALS. J Neurosci 33: 11588-11598. doi: 10.1523/JNEUROSCI.5385-12.2013
![]() |
[41] |
Kikuchi H, Almer G, Yamashita S, et al. (2006) Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model. Proc Natl Acad Sci U S A 103: 6025-6030. doi: 10.1073/pnas.0509227103
![]() |
[42] |
Sun S, Sun Y, Ling SC, et al. (2015) Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS. Proc Natl Acad Sci U S A 112: E6993-E7002. doi: 10.1073/pnas.1520639112
![]() |
[43] |
Ito Y, Yamada M, Tanaka H, et al. (2009) Involvement of CHOP, an ER-stress apoptotic mediator, in both human sporadic ALS and ALS model mice. Neurobiol Dis 36: 470-476. doi: 10.1016/j.nbd.2009.08.013
![]() |
[44] |
Nishitoh H, Kadowaki H, Nagai A, et al. (2008) ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. Genes Dev 22: 1451-1464. doi: 10.1101/gad.1640108
![]() |
[45] | Pokrishevsky E, Grad LI, Yousefi M, et al. (2012) Aberrant localization of FUS and TDP43 is associated with misfolding of SOD1 in amyotrophic lateral sclerosis. PLoS One 7: 1-9. |
[46] |
Dimos JT, Rodolfa KT, Niakan KK, et al. (2008) Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321: 1218-1221. doi: 10.1126/science.1158799
![]() |
[47] |
Chen H, Qian K, Du Z, et al. (2014) Modeling ALS with iPSCs reveals that mutant SOD1 misregulates neurofilament balance in motor neurons. Cell Stem Cell 14: 796-809. doi: 10.1016/j.stem.2014.02.004
![]() |
[48] |
Kiskinis E, Sandoe J, Williams LA, et al. (2014) Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1. Cell Stem Cell 14: 781-795. doi: 10.1016/j.stem.2014.03.004
![]() |
[49] | Neary D, Snowden JS, Mann DM (2000) Classification and description of frontotemporal dementias. Ann N Y Acad Sci 920: 46-51. |
[50] |
Higashi S, Iseki E, Yamamoto R, et al. (2007) Concurrence of TDP-43, tau and α-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res 1184: 284-294. doi: 10.1016/j.brainres.2007.09.048
![]() |
[51] | Ou SH, Wu F, Harrich D, et al. (1995) Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J Virol 69: 3584-3596. |
[52] |
Lu Y, Ferris J, Gao FB (2009) Frontotemporal dementia and amyotrophic lateral sclerosis-associated disease protein TDP-43 promotes dendritic branching. Mol Brain 2: 30. doi: 10.1186/1756-6606-2-30
![]() |
[53] |
Winton MJ, Igaz LM, Wong MM, et al. (2008) Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation. J Biol Chem 283: 13302-13309. doi: 10.1074/jbc.M800342200
![]() |
[54] |
Kuo PH, Doudeva LG, Wang YT, et al. (2009) Structural insights into TDP-43 in nucleic-acid binding and domain interactions. Nucleic Acids Res 37: 1799-1808. doi: 10.1093/nar/gkp013
![]() |
[55] |
Buratti E, Brindisi A, Giombi M, et al. (2005) TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail: an important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon9 splicing. J Biol Chem 280: 37572-37584. doi: 10.1074/jbc.M505557200
![]() |
[56] |
Kabashi E, Valdmanis PN, Dion P, et al. (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40: 572-574. doi: 10.1038/ng.132
![]() |
[57] |
Johnson BS, McCaffery JM, Lindquist S, et al. (2008) A yeast TDP-43 proteinopathy model: Exploring the molecular determinants of TDP-43 aggregation and cellular toxicity. Proc Natl Acad Sci U S A 105: 6439-6444. doi: 10.1073/pnas.0802082105
![]() |
[58] |
Hasegawa M, Arai T, Nonaka T, et al. (2008) Phosphorylated TDP-43 in frontotemporal lobar degeneration and ALS. Ann Neurol 64: 60-70. doi: 10.1002/ana.21425
![]() |
[59] |
Kadokura A, Yamazaki T, Kakuda S, et al. (2009) Phosphorylation-dependent TDP-43 antibody detects intraneuronal dot-like structures showing morphological characters of granulovacuolar degeneration. Neurosci Lett 463: 87-92. doi: 10.1016/j.neulet.2009.06.024
![]() |
[60] |
Igaz LM, Kwong LK, Chen-Plotkin A, et al. (2009) Expression of TDP-43 C-terminal fragments in vitro recapitulates pathological features of TDP-43 proteinopathies. J Biol Chem 284: 8516-8524. doi: 10.1074/jbc.M809462200
![]() |
[61] |
Zhang YJ, Xu YF, Cook C, et al. (2009) Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc Natl Acad Sci U S A 106: 7607-7612. doi: 10.1073/pnas.0900688106
![]() |
[62] |
Arai T, Hasegawa M, Akiyama H, et al. (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351: 602-611. doi: 10.1016/j.bbrc.2006.10.093
![]() |
[63] |
Dormann D, Capell A, Carlson AM, et al. (2009) Proteolytic processing of TAR DNA binding protein-43 by caspases produces C-terminal fragments with disease defining properties independent of progranulin. J Neurochem 110: 1082-1094. doi: 10.1111/j.1471-4159.2009.06211.x
![]() |
[64] |
Wils H, Kleinberger G, Janssens J, et al. (2010) TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A 107: 3858-3863. doi: 10.1073/pnas.0912417107
![]() |
[65] |
Giordana MT, Piccinini M, Grifoni S, et al. (2010) TDP-43 redistribution is an early event in sporadic amyotrophic lateral sclerosis. Brain Pathol 20: 351-360. doi: 10.1111/j.1750-3639.2009.00284.x
![]() |
[66] | Udan M, Baloh RH (2011) Implications of the prion-related Q/N domains in TDP-43 and FUS. Prion 5: 1-5. |
[67] |
Nonaka T, Masuda-Suzukake M, Arai T, et al. (2013) Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep 4: 124-134. doi: 10.1016/j.celrep.2013.06.007
![]() |
[68] |
Walker AK, Soo KY, Sundaramoorthy V, et al. (2013) ALS-associated TDP-43 induces endoplasmic reticulum stress, which drives cytoplasmic TDP-43 accumulation and stress granule formation. PLoS One 8: e81170. doi: 10.1371/journal.pone.0081170
![]() |
[69] |
Polymenidou M, Lagier-Tourenne C, Hutt KR, et al. (2011) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci 14: 459-468. doi: 10.1038/nn.2779
![]() |
[70] |
Watanabe S, Kaneko K, Yamanaka K (2013) Accelerated disease onset with stabilized familial amyotrophic lateral ssclerosis (ALS)-linked mutant TDP-43 proteins. J Biol Chem 288: 3641-3654. doi: 10.1074/jbc.M112.433615
![]() |
[71] |
Iguchi Y, Katsuno M, Niwa J, et al. (2013) Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain 136: 1371-1382. doi: 10.1093/brain/awt029
![]() |
[72] |
Wegorzewska I, Bell S, Cairns NJ, et al. (2009) TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A 106: 18809-18814. doi: 10.1073/pnas.0908767106
![]() |
[73] |
Feiguin F, Godena VK, Romano G, et al. (2009) Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior. FEBS Lett 583: 1586-1592. doi: 10.1016/j.febslet.2009.04.019
![]() |
[74] | Alami NH, Smith RB, Carrasco MA, et al. (2013) Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 81: 536-543. |
[75] | Xia Q, Wang H, Hao Z, et al. (2015) TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion. EMBO J 35: 1-22. |
[76] |
Armakola M, Higgins MJ, Figley MD, et al. (2012) Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. Nat Genet 44: 1302-1309. doi: 10.1038/ng.2434
![]() |
[77] |
Elden AC, Kim HJ, Hart MP, et al. (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466: 1069-1075. doi: 10.1038/nature09320
![]() |
[78] |
Liu-Yesucevitz L, Lin AY, Ebata A, et al. (2014) ALS-linked mutations enlarge TDP-43-enriched neuronal RNA granules in the dendritic arbor. J Neurosci 34: 4167-4174. doi: 10.1523/JNEUROSCI.2350-13.2014
![]() |
[79] |
Crozat A, Aman P, Mandahl N, et al. (1993) Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature 363: 640-644. doi: 10.1038/363640a0
![]() |
[80] |
Rabbits TH, Forster A, Larson R, et al. (1993) Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t (12; 16) in malignant liposarcoma. Nat Genet 4: 175-180. doi: 10.1038/ng0693-175
![]() |
[81] |
Vance C, Rogelj B, Hortobágyi T, et al. (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis Type 6. Science 323: 1208-1211. doi: 10.1126/science.1165942
![]() |
[82] |
Kwiatkowski TJ, Bosco DA, Leclerc AL, et al. (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323: 1205-1208. doi: 10.1126/science.1166066
![]() |
[83] |
Neumann M, Rademakers R, Roeber S, et al. (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132: 2922-2931. doi: 10.1093/brain/awp214
![]() |
[84] | Kovar H (2011) The two faces of the FUS/EWS/TAF15 protein family. Sarcoma 2011: 1-13. |
[85] |
Couthouis J, Hart MP, Erion R, et al. (2012) Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum Mol Genet 21: 2899-2911. doi: 10.1093/hmg/dds116
![]() |
[86] |
Lee BJ, Cansizoglu AE, Süel KE, et al. (2006) Rules for Nuclear Localization Sequence Recognition by Karyopherinβ2. Cell 126: 543-558. doi: 10.1016/j.cell.2006.05.049
![]() |
[87] |
Dormann D, Rodde R, Edbauer D, et al. (2010) ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J 29: 2841-2857. doi: 10.1038/emboj.2010.143
![]() |
[88] |
Dormann D, Madl T, Valori CF, et al. (2012) Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS. EMBO J 31: 4258-4275. doi: 10.1038/emboj.2012.261
![]() |
[89] |
Snowden JS, Hu Q, Rollinson S, et al. (2011) The most common type of FTLD-FUS (aFTLD-U) is associated with a distinct clinical form of frontotemporal dementia but is not related to mutations in the FUS gene. Acta Neuropathol 122: 99-110. doi: 10.1007/s00401-011-0816-0
![]() |
[90] |
Urwin H, Josephs KA, Rohrer JD, et al. (2010) FUS pathology defines the majority of tau-and TDP-43-negative frontotemporal lobar degeneration. Acta Neuropathol 120: 33-41. doi: 10.1007/s00401-010-0698-6
![]() |
[91] |
Brelstaff J, Lashley T, Holton JL, et al. (2011) Transportin1: a marker of FTLD-FUS. Acta Neuropathol 122: 591-600. doi: 10.1007/s00401-011-0863-6
![]() |
[92] |
Davidson YS, Robinson AC, Hu Q, et al. (2013) Nuclear carrier and RNA-binding proteins in frontotemporal lobar degeneration associated with fused in sarcoma (FUS) pathological changes. Neuropathol Appl Neurobiol 39: 157-165. doi: 10.1111/j.1365-2990.2012.01274.x
![]() |
[93] |
Kuroda M, Sok J, Webb L, et al. (2000) Male sterility and enhanced radiation sensitivity in TLS(-/-) mice. EMBO J 19: 453-462. doi: 10.1093/emboj/19.3.453
![]() |
[94] |
Hicks GG, Singh N, Nashabi A, et al. (2000) Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death. Nat Genet 24: 175-179. doi: 10.1038/72842
![]() |
[95] |
Kabashi E, Bercier V, Lissouba A, et al. (2011) FUS and TARDBP but not SOD1 interact in genetic models of amyotrophic lateral sclerosis. PLoS Genet 7: e1002214. doi: 10.1371/journal.pgen.1002214
![]() |
[96] |
Mitchell JC, McGoldrick P, Vance C, et al. (2013) Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion. Acta Neuropathol 125: 273-288. doi: 10.1007/s00401-012-1043-z
![]() |
[97] |
Levine TP, Daniels RD, Gatta AT, et al. (2013) The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics 29: 499-503. doi: 10.1093/bioinformatics/bts725
![]() |
[98] |
Farg MA, Sundaramoorthy V, Sultana JM, et al. (2014) C9ORF72, implicated in amytrophic lateral sclerosis and frontemporal dementia, regulates endosomal trafficking. Hum Mol Genet 23: 3579-3595. doi: 10.1093/hmg/ddu068
![]() |
[99] |
Donnelly CJ, Zhang PW, Pham JT, et al. (2013) RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80: 415-428. doi: 10.1016/j.neuron.2013.10.015
![]() |
[100] |
Therrien M, Rouleau GA, Dion PA, et al. (2013) Deletion of C9ORF72 results in motor neuron degeneration and stress sensitivity in C. elegans. PLoS One 8: 1-10. doi: 10.1371/journal.pone.0083450
![]() |
[101] | Ciura S, Lattante S, Le Ber I, et al. (2013) Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis. Ann Neurol 74: 180-187. |
[102] |
Koppers M, Blokhuis AM, Westeneng H-J, et al. (2015) C9orf72 ablation in mice does not cause motor neuron degenerateon or motor deficit. Ann Neurol 78: 426-438. doi: 10.1002/ana.24453
![]() |
[103] | Ranum LPW, Cooper TA (2006) RNA-mediated neuromascular disorders. Annu Rev Neurosci 29: 259-77. |
[104] |
Xu Z, Poidevin M, Li X, et al. (2013) Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc Natl Acad Sci U S A 110: 7778-7783. doi: 10.1073/pnas.1219643110
![]() |
[105] | Haeusler AR, Donnelly CJ, Periz G, et al. (2014) C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507: 195-200. |
[106] | Zu T, Gibbens B, Doty NS, et al. (2010) Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A 108: 260-265. |
[107] |
Mori K, Weng S, Arzberger T, et al. (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339: 1335-1339. doi: 10.1126/science.1232927
![]() |
[108] |
Mori K, Lammich S, Mackenzie IR, et al. (2013) hnRNP A3 bind to GGGGCC repeats and is a constituent of p62-positive/TDP-43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta. Neuropathol 125: 413-423. doi: 10.1007/s00401-013-1088-7
![]() |
[109] |
Ash PEA, Bieniek KF, Gendron TF, et al. (2013) Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77: 639-646. doi: 10.1016/j.neuron.2013.02.004
![]() |
[110] |
Zhang YJ, Jansen-West K, Xu YF, et al. (2014) Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol 128: 505-524. doi: 10.1007/s00401-014-1336-5
![]() |
[111] |
Mizielinska S, Grönke S, Niccoli T, et al. (2014) C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 345: 1192-1195. doi: 10.1126/science.1256800
![]() |
[112] |
Tran H, Almeida S, Moore J, et al. (2015) Differential toxicity of nuclear RNA foci versus dipeptide repeat proteins in a Drosophila model of C9ORF72 FTD/ALS. Neuron 87: 1207-1214 doi: 10.1016/j.neuron.2015.09.015
![]() |
[113] | Chew J, Gendron TF, Prudencio M, et al. (2015) C9ORF72 repeat expansion in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348: 2-6. |
[114] |
O’Rourke JG, Bogdanik L, Muhammad AKMG, et al. (2015) C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD. Neuron 88: 892-901. doi: 10.1016/j.neuron.2015.10.027
![]() |
[115] |
Zhang K, Donnelly CJ, Haeusler AR, et al. (2015) The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525: 56-61. doi: 10.1038/nature14973
![]() |
[116] |
Freibaum BD, Lu Y, Lopez-gonzalez R, et al. (2015) GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525: 129-133. doi: 10.1038/nature14974
![]() |
[117] |
Jovičić A, Mertens J, Boeynaems S, et al. (2015) Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci 18: 1226-1229. doi: 10.1038/nn.4085
![]() |
[118] |
Rezaie T, Child A, Hitchings R, et al. (2002) Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295: 1077-1079. doi: 10.1126/science.1066901
![]() |
[119] |
Zhu G, Wu CJ, Zhao Y, et al. (2007) Optineurin negatively regulates TNFα- induced NF-κB activation by competing with NEMO for ubiquitinated RIP. Curr Biol 17: 1438-1443. doi: 10.1016/j.cub.2007.07.041
![]() |
[120] | Wild P, Farhan H, McEwan DG, et al. (2011) Phosphorylation of the autophagy receptor Optineurin restricts salmonella growth. Science 333: 228-233. |
[121] |
Sahlender DA, Roberts RC, Arden SD, et al. (2005) Optineurin links myosin VI to the Golgi complex and is involved in Golgi organization and exocytosis. J Cell Biol 169: 285-295. doi: 10.1083/jcb.200501162
![]() |
[122] |
Wild P, Farhan H, McEwan DG, et al. (2011) Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333: 228-233. doi: 10.1126/science.1205405
![]() |
[123] | Deng HX, Bigio EH, Zhai H, et al. (2012) Differential involvement of Optineurin in amyotrophic lateral sclerosis with or without SOD1 mutations. Arch Neurol 68: 1057-1061. |
[124] |
Ito H, Fujita K, Nakamura M, et al. (2011) Optineurin is co-localized with FUS in basophilic inclusions of ALS with FUS mutation and in basophilic inclusion body disease. Acta Neuropathol 121: 555-557. doi: 10.1007/s00401-011-0809-z
![]() |
[125] | Williams KL, Warraich ST, Yang S, et al. (2012) UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic lateral sclerosis. Neurobiol Aging 33: 2527.e3-10. |
[126] |
Seok Ko H, Uehara T, Tsuruma K, et al. (2004) Ubiquilin interacts with ubiquitylated proteins and proteasome through its ubiquitin-associated and ubiquitin-like domains. FEBS Lett 566: 110-114. doi: 10.1016/j.febslet.2004.04.031
![]() |
[127] |
Ritson GP, Custer SK, Freibaum BD, et al. (2010) TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97. J Neurosci 30: 7729-7739. doi: 10.1523/JNEUROSCI.5894-09.2010
![]() |
[128] |
Ye Y, Shibata Y, Yun C, et al. (2004) A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429: 841-847. doi: 10.1038/nature02656
![]() |
[129] |
Ye Y, Shibata Y, Kikkert M, et al. (2005) Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane. Proc Natl Acad Sci U S A 102: 14132-14138. doi: 10.1073/pnas.0505006102
![]() |
[130] |
Song C, Wang Q, Li CH (2003) ATPase Activity of p97-Valosin-containing Protein (VCP). D2 mediates the major enzyme activity, and D1 contributes to the heat-induced activity. J Biol Chem 278: 3648-3655. doi: 10.1074/jbc.M208422200
![]() |
[131] |
Carvalho P, Stanley AM, Rapoport TA (2010) Retrotranslocation of a misfolded luminal ER protein by the ubiquitin-ligase Hrd1p. Cell 143: 579-591. doi: 10.1016/j.cell.2010.10.028
![]() |
[132] |
Bilican B, Serio A, Barmada SJ, et al. (2012) Mutant induced plu- ripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proc Natl Acad Sci U S A 109: 5803-5808. doi: 10.1073/pnas.1202922109
![]() |
[133] |
Liu X, Chen J, Liu W, et al. (2015) The fused in sarcoma protein forms cytoplasmic aggregates in motor neurons derived from integration-free induced pluripotent stem cells generated from a patient with familial amyotrophic lateral sclerosis carrying the FUS-P525L mutation. Neurogenetics 16: 223-231. doi: 10.1007/s10048-015-0448-y
![]() |
[134] |
Mackenzie IR, Bigio EH, Ince PG, et al. (2007) Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 61: 427-434. doi: 10.1002/ana.21147
![]() |
[135] |
Yamanaka K, Chun SJ, Boillee S, et al. (2008) Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11: 251-253. doi: 10.1038/nn2047
![]() |