Journal articles: 'Mutant FUS'

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Humphrey, Jack, Nicol Birsa, Carmelo Milioto, Martha McLaughlin, Agnieszka M. Ule, David Robaldo, Andrea B. Eberle, et al. "FUS ALS-causative mutations impair FUS autoregulation and splicing factor networks through intron retention." Nucleic Acids Research 48, no. 12 (June 1, 2020): 6889–905. http://dx.doi.org/10.1093/nar/gkaa410.

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Abstract Mutations in the RNA-binding protein FUS cause amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease. FUS plays a role in numerous aspects of RNA metabolism, including mRNA splicing. However, the impact of ALS-causative mutations on splicing has not been fully characterized, as most disease models have been based on overexpressing mutant FUS, which will alter RNA processing due to FUS autoregulation. We and others have recently created knockin models that overcome the overexpression problem, and have generated high depth RNA-sequencing on FUS mutants in parallel to FUS knockout, allowing us to compare mutation-induced changes to genuine loss of function. We find that FUS-ALS mutations induce a widespread loss of function on expression and splicing. Specifically, we find that mutant FUS directly alters intron retention levels in RNA-binding proteins. Moreover, we identify an intron retention event in FUS itself that is associated with its autoregulation. Altered FUS levels have been linked to disease, and we show here that this novel autoregulation mechanism is altered by FUS mutations. Crucially, we also observe this phenomenon in other genetic forms of ALS, including those caused by TDP-43, VCP and SOD1 mutations, supporting the concept that multiple ALS genes interact in a regulatory network.

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Schwartz, Jacob C., Elaine R. Podell, Steve S. W. Han, James D. Berry, Kevin C. Eggan, and Thomas R. Cech. "FUS is sequestered in nuclear aggregates in ALS patient fibroblasts." Molecular Biology of the Cell 25, no. 17 (September 2014): 2571–78. http://dx.doi.org/10.1091/mbc.e14-05-1007.

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Mutations in the RNA-binding protein FUS have been shown to cause the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We investigate whether mutant FUS protein in ALS patient–derived fibroblasts affects normal FUS functions in the nucleus. We investigated fibroblasts from two ALS patients possessing different FUS mutations and a normal control. Fibroblasts from these patients have their nuclear FUS protein trapped in SDS-resistant aggregates. Genome-wide analysis reveals an inappropriate accumulation of Ser-2 phosphorylation on RNA polymerase II (RNA Pol II) near the transcription start sites of 625 genes for ALS patient cells and after small interfering RNA (siRNA) knockdown of FUS in normal fibroblasts. Furthermore, both the presence of mutant FUS protein and siRNA knockdown of wild-type FUS correlate with altered distribution of RNA Pol II within fibroblast nuclei. A loss of FUS function in orchestrating Ser-2 phosphorylation of the CTD of RNA Pol II is detectable in ALS patient–derived fibroblasts expressing mutant FUS protein, even when the FUS protein remains largely nuclear. A likely explanation for this loss of function is the aggregation of FUS protein in nuclei. Thus our results suggest a specific mechanism by which mutant FUS can have biological consequences other than by the formation of cytoplasmic aggregates.

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Kamelgarn, Marisa, Jing Chen, Lisha Kuang, Huan Jin, Edward J. Kasarskis, and Haining Zhu. "ALS mutations of FUS suppress protein translation and disrupt the regulation of nonsense-mediated decay." Proceedings of the National Academy of Sciences 115, no. 51 (November 19, 2018): E11904—E11913. http://dx.doi.org/10.1073/pnas.1810413115.

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Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by preferential motor neuron death. Approximately 15% of ALS cases are familial, and mutations in the fused in sarcoma (FUS) gene contribute to a subset of familial ALS cases. FUS is a multifunctional protein participating in many RNA metabolism pathways. ALS-linked mutations cause a liquid–liquid phase separation of FUS protein in vitro, inducing the formation of cytoplasmic granules and inclusions. However, it remains elusive what other proteins are sequestered into the inclusions and how such a process leads to neuronal dysfunction and degeneration. In this study, we developed a protocol to isolate the dynamic mutant FUS-positive cytoplasmic granules. Proteomic identification of the protein composition and subsequent pathway analysis led us to hypothesize that mutant FUS can interfere with protein translation. We demonstrated that the ALS mutations in FUS indeed suppressed protein translation in N2a cells expressing mutant FUS and fibroblast cells derived from FUS ALS cases. In addition, the nonsense-mediated decay (NMD) pathway, which is closely related to protein translation, was altered by mutant FUS. Specifically, NMD-promoting factors UPF1 and UPF3b increased, whereas a negative NMD regulator, UPF3a, decreased, leading to the disruption of NMD autoregulation and the hyperactivation of NMD. Alterations in NMD factors and elevated activity were also observed in the fibroblast cells of FUS ALS cases. We conclude that mutant FUS suppresses protein biosynthesis and disrupts NMD regulation, both of which likely contribute to motor neuron death.

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Mallik, Moushami, Marica Catinozzi, Clemens B. Hug, Li Zhang, Marina Wagner, Julia Bussmann, Jonas Bittern, et al. "Xrp1 genetically interacts with the ALS-associated FUS orthologue caz and mediates its toxicity." Journal of Cell Biology 217, no. 11 (September 12, 2018): 3947–64. http://dx.doi.org/10.1083/jcb.201802151.

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Cabeza (caz) is the single Drosophila melanogaster orthologue of the human FET proteins FUS, TAF15, and EWSR1, which have been implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we identified Xrp1, a nuclear chromatin-binding protein, as a key modifier of caz mutant phenotypes. Xrp1 expression was strongly up-regulated in caz mutants, and Xrp1 heterozygosity rescued their motor defects and life span. Interestingly, selective neuronal Xrp1 knockdown was sufficient to rescue, and neuronal Xrp1 overexpression phenocopied caz mutant phenotypes. The caz/Xrp1 genetic interaction depended on the functionality of the AT-hook DNA-binding domain in Xrp1, and the majority of Xrp1-interacting proteins are involved in gene expression regulation. Consistently, caz mutants displayed gene expression dysregulation, which was mitigated by Xrp1 heterozygosity. Finally, Xrp1 knockdown substantially rescued the motor deficits and life span of flies expressing ALS mutant FUS in motor neurons, implicating gene expression dysregulation in ALS-FUS pathogenesis.

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Rhine, Kevin, Jaya Sarkar, Amirhossein Ghanbari Niaki, Xinyi Cai, Gabby Vidaurre, and Sua Myong. "Wild-Type Fus Rescues Altered RNA Binding of ALS-Linked FUS Mutant." Biophysical Journal 116, no. 3 (February 2019): 213a. http://dx.doi.org/10.1016/j.bpj.2018.11.1177.

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Perrotti, Danilo, Angela Iervolino, Vincenzo Cesi, Maria Cirinná, Silvia Lombardini, Emanuela Grassilli, Silvia Bonatti, Pier Paolo Claudio, and Bruno Calabretta. "BCR-ABL Prevents c-Jun-Mediated and Proteasome-Dependent FUS (TLS) Proteolysis through a Protein Kinase CβII-Dependent Pathway." Molecular and Cellular Biology 20, no. 16 (August 15, 2000): 6159–69. http://dx.doi.org/10.1128/mcb.20.16.6159-6169.2000.

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ABSTRACT The DNA binding activity of FUS (also known as TLS), a nuclear pro-oncogene involved in multiple translocations, is regulated by BCR-ABL in a protein kinase CβII (PKCβII)-dependent manner. We show here that in normal myeloid progenitor cells FUS, although not visibly ubiquitinated, undergoes proteasome-dependent degradation, whereas in BCR-ABL-expressing cells, degradation is suppressed by PKCβII phosphorylation. Replacement of serine 256 with the phosphomimetic aspartic acid prevents proteasome-dependent proteolysis of FUS, while the serine-256-to-alanine FUS mutant is unstable and susceptible to degradation. Ectopic expression of the phosphomimetic S256D FUS mutant in granulocyte colony-stimulating factor-treated 32Dcl3 cells induces massive apoptosis and inhibits the differentiation of the cells escaping cell death, while the degradation-prone S256A mutant has no effect on either survival or differentiation. FUS proteolysis is induced by c-Jun, is suppressed by BCR-ABL or Jun kinase 1, and does not depend on c-Jun transactivation potential, ubiquitination, or its interaction with Jun kinase 1. In addition, c-Jun-induced FUS proteasome-dependent degradation is enhanced by heterogeneous nuclear ribonucleoprotein (hnRNP) A1 and depends on the formation of a FUS-Jun-hnRNP A1-containing complex and on lack of PKCβII phosphorylation at serine 256 but not on FUS ubiquitination. Thus, novel mechanisms appear to be involved in the degradation of FUS in normal myeloid cells; moreover, the ability of the BCR-ABL oncoprotein to suppress FUS degradation by the induction of posttranslational modifications might contribute to the phenotype of BCR-ABL-expressing hematopoietic cells.

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Brizzio, V., A. E. Gammie, G. Nijbroek, S. Michaelis, and M. D. Rose. "Cell fusion during yeast mating requires high levels of a-factor mating pheromone." Journal of Cell Biology 135, no. 6 (December 15, 1996): 1727–39. http://dx.doi.org/10.1083/jcb.135.6.1727.

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During conjugation, two yeast cells fuse to form a single zygote. Cell fusion requires extensive remodeling of the cell wall, both to form a seal between the two cells and to remove the intervening material. The two plasma membranes then fuse to produce a continuous cytoplasm. We report the characterization of two cell fusion defective (Fus-) mutants, fus5 and fus8, isolated previously in our laboratory. Fluorescence and electron microscopy demonstrated that the fus5 and fus8 mutant zygotes were defective for cell wall remodeling/removal but not plasma membrane fusion. Strikingly, fus5 and fus8 were a specific; both mutations caused the mutant phenotype when present in the MATa parent but not in the MAT alpha parent. Consistent with an a-specific defect, the fus5 and fus8 mutants produced less a-factor than the isogenic wild-type strain. FUS5 and FUS8 were determined to be allelic to AXL1 and RAM1, respectively, two genes known to be required for biogenesis of a-factor. Several experiments demonstrated that the partial defect in a-factor production resulted in the Fus- phenotype. First, overexpression of a-factor in the fus mutants suppressed the Fus- defect. Second, matings to an MAT alpha partner supersensitive to mating pheromone (sst2 delta) suppressed the Fus- defect in trans. Finally, the gene encoding a-factor, MFA1, was placed under the control of a repressible promoter; reduced levels of wild-type a-factor caused an identical cell fusion defect during mating. We conclude that high levels of pheromone are required as one component of the signal for prezygotes to initiate cell fusion.

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Ichikawa, Hitoshi, Kimiko Shimizu, Rieko Katsu, and Misao Ohki. "Dual Transforming Activities of the FUS (TLS)-ERG Leukemia Fusion Protein Conferred by Two N-Terminal Domains of FUS (TLS)." Molecular and Cellular Biology 19, no. 11 (November 1, 1999): 7639–50. http://dx.doi.org/10.1128/mcb.19.11.7639.

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ABSTRACT The FUS (TLS)-ERG chimeric protein associated with t(16;21)(p11;q22) acute myeloid leukemia is structurally similar to the Ewing’s sarcoma chimeric transcription factor EWS-ERG. We found that both FUS-ERG and EWS-ERG could induce anchorage-independent proliferation of the mouse fibroblast cell line NIH 3T3. However, only FUS-ERG was able to inhibit the differentiation into neutrophils of a mouse myeloid precursor cell line L-G and induce its granulocyte colony-stimulating factor-dependent growth. We constructed several deletion mutants of FUS-ERG lacking a part of the N-terminal FUS region. A deletion mutant lacking the region between amino acids 1 and 173 (exons 1 to 5) lost the NIH 3T3-transforming activity but retained the L-G-transforming activity. On the other hand, a mutant lacking the region between amino acids 174 and 265 (exons 6 and 7) lost the L-G-transforming activity but retained the NIH 3T3-transforming activity. These results indicate that the N-terminal region of FUS contains two independent functional domains required for the NIH 3T3 and L-G transformation, which we named TR1 and TR2, respectively. Although EWS intrinsically possessed the TR2 domain, the EWS-ERG construct employed lacked the EWS sequence containing this domain. Since the TR2 domain is always found in chimeric proteins identified from t(16;21) leukemia patients but not in chimeric proteins from Ewing’s sarcoma patients, it seems that the TR2 function is required only for the leukemogenic potential. In addition, we identified three cellular genes whose expression was altered by ectopic expression of FUS-ERG and found that these are regulated in either a TR1-dependent or a TR2-dependent manner. These results suggest that FUS-ERG may activate two independent oncogenic pathways during the leukemogenic process by modulating the expression of two different groups of genes simultaneously.

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Kuang, Lisha, Marisa Kamelgarn, Alexandra Arenas, Jozsef Gal, Deborah Taylor, Weiming Gong, Martin Brown, Daret St. Clair, Edward J. Kasarskis, and Haining Zhu. "Clinical and experimental studies of a novel P525R FUS mutation in amyotrophic lateral sclerosis." Neurology Genetics 3, no. 4 (July 20, 2017): e172. http://dx.doi.org/10.1212/nxg.0000000000000172.

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Objective:To describe the clinical features of a novel fused in sarcoma (FUS) mutation in a young adult female amyotrophic lateral sclerosis (ALS) patient with rapid progression of weakness and to experimentally validate the consequences of the P525R mutation in cellular neuronal models.Methods:We conducted sequencing of genomic DNA from the index patient and her family members. Immunocytochemistry was performed in various cellular models to determine whether the newly identified P525R mutant FUS protein accumulated in cytoplasmic inclusions. Clinical features of the index patient were compared with 19 other patients with ALS carrying the P525L mutation in the same amino acid position.Results:A novel mutation c.1574C>G (p.525P>R) in the FUS gene was identified in the index patient. The clinical symptoms are similar to those in familial ALS patients with the P525L mutation at the same position. The P525R mutant FUS protein showed cytoplasmic localization and formed large stress granule–like cytoplasmic inclusions in multiple cellular models.Conclusions:The clinical features of the patient and the cytoplasmic inclusions of the P525R mutant FUS protein strengthen the notion that mutations at position 525 of the FUS protein result in a coherent phenotype characterized by juvenile or young adult onset, rapid progression, variable positive family history, and female preponderance.

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Zhang, Xue, Fengchao Wang, Yi Hu, Runze Chen, Dawei Meng, Liang Guo, Hailong Lv, Jisong Guan, and Yichang Jia. "In vivo stress granule misprocessing evidenced in a FUS knock-in ALS mouse model." Brain 143, no. 5 (May 1, 2020): 1350–67. http://dx.doi.org/10.1093/brain/awaa076.

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Abstract Many RNA-binding proteins, including TDP-43, FUS, and TIA1, are stress granule components, dysfunction of which causes amyotrophic lateral sclerosis (ALS). However, whether a mutant RNA-binding protein disrupts stress granule processing in vivo in pathogenesis is unknown. Here we establish a FUS ALS mutation, p.R521C, knock-in mouse model that carries impaired motor ability and late-onset motor neuron loss. In disease-susceptible neurons, stress induces mislocalization of mutant FUS into stress granules and upregulation of ubiquitin, two hallmarks of disease pathology. Additionally, stress aggravates motor performance decline in the mutant mouse. By using two-photon imaging in TIA1-EGFP transduced animals, we document more intensely TIA1-EGFP-positive granules formed hours but cleared weeks after stress challenge in neurons in the mutant cortex. Moreover, neurons with severe granule misprocessing die days after stress challenge. Therefore, we argue that stress granule misprocessing is pathogenic in ALS, and the model we provide here is sound for further disease mechanistic study.

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Birsa, Nicol, Agnieszka M. Ule, Maria Giovanna Garone, Brian Tsang, Francesca Mattedi, P. Andrew Chong, Jack Humphrey, et al. "FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation." Science Advances 7, no. 30 (July 2021): eabf8660. http://dx.doi.org/10.1126/sciadv.abf8660.

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FUsed in Sarcoma (FUS) is a multifunctional RNA binding protein (RBP). FUS mutations lead to its cytoplasmic mislocalization and cause the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Here, we use mouse and human models with endogenous ALS-associated mutations to study the early consequences of increased cytoplasmic FUS. We show that in axons, mutant FUS condensates sequester and promote the phase separation of fragile X mental retardation protein (FMRP), another RBP associated with neurodegeneration. This leads to repression of translation in mouse and human FUS-ALS motor neurons and is corroborated in vitro, where FUS and FMRP copartition and repress translation. Last, we show that translation of FMRP-bound RNAs is reduced in vivo in FUS-ALS motor neurons. Our results unravel new pathomechanisms of FUS-ALS and identify a novel paradigm by which mutations in one RBP favor the formation of condensates sequestering other RBPs, affecting crucial biological functions, such as protein translation.

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Wang, Haibo, and Muralidhar L. Hegde. "New Mechanisms of DNA Repair Defects in Fused in Sarcoma–Associated Neurodegeneration: Stage Set for DNA Repair-Based Therapeutics?" Journal of Experimental Neuroscience 13 (January 2019): 117906951985635. http://dx.doi.org/10.1177/1179069519856358.

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Genome damage and defective DNA repair are etiologically linked to several neurodegenerative disorders, including fused in sarcoma (FUS)–associated amyotrophic lateral sclerosis (ALS). However, the underlying mechanisms remain enigmatic, which is a roadblock for exploiting genome repair-targeted therapies. Our recent studies identified defects in DNA nick ligation and oxidative damage repair caused by mutations in the RNA/DNA-binding protein FUS in familial ALS patients. In healthy neurons, FUS protects the genome by facilitating PARP1-dependent recruitment of XRCC1/DNA Ligase IIIα (LigIII) to oxidized genome sites and activating LigIII via direct interaction. This is a critical step in the repair of oxidative genome damage, a foremost challenge for postmitotic neurons due to their high oxygen consumption. We discovered that mutant FUS significantly inhibited the recruitment of XRCC1/LigIII to DNA strand breaks, causing defects in DNA ligation during the repair of oxidative DNA damage, which contributed to neurodegeneration. While the FUS loss of function was responsible for the repair defects, increased oxidative genome damage due to mutant FUS aggregation could exacerbate the phenomenon. We highlight how these new molecular insights into previously undescribed DNA repair defect linked to FUS-associated neurodegeneration could provide an important opportunity for exploring DNA repair-based therapeutic avenues.

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Stronati, Eleonora, Stefano Biagioni, Mario Fiore, Mauro Giorgi, Giancarlo Poiana, Camilla Toselli, and Emanuele Cacci. "Wild-Type and Mutant FUS Expression Reduce Proliferation and Neuronal Differentiation Properties of Neural Stem Progenitor Cells." International Journal of Molecular Sciences 22, no. 14 (July 15, 2021): 7566. http://dx.doi.org/10.3390/ijms22147566.

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Nervous system development involves proliferation and cell specification of progenitor cells into neurons and glial cells. Unveiling how this complex process is orchestrated under physiological conditions and deciphering the molecular and cellular changes leading to neurological diseases is mandatory. To date, great efforts have been aimed at identifying gene mutations associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Mutations in the RNA/DNA binding protein Fused in Sarcoma/Translocated in Liposarcoma (FUS/TLS) have been associated with motor neuron degeneration in rodents and humans. Furthermore, increased levels of the wild-type protein can promote neuronal cell death. Despite the well-established causal link between FUS mutations and ALS, its role in neural cells remains elusive. In order to shed new light on FUS functions we studied its role in the control of neural stem progenitor cell (NSPC) properties. Here, we report that human wild-type Fused in Sarcoma (WT FUS), exogenously expressed in mouse embryonic spinal cord-derived NSPCs, was localized in the nucleus, caused cell cycle arrest in G1 phase by affecting cell cycle regulator expression, and strongly reduced neuronal differentiation. Furthermore, the expression of the human mutant form of FUS (P525L-FUS), associated with early-onset ALS, drives the cells preferentially towards a glial lineage, strongly reducing the number of developing neurons. These results provide insight into the involvement of FUS in NSPC proliferation and differentiation into neurons and glia.

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Vance, Caroline, Emma L. Scotter, Agnes L. Nishimura, Claire Troakes, Jacqueline C. Mitchell, Claudia Kathe, Hazel Urwin, et al. "ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within cytoplasmic stress granules." Human Molecular Genetics 22, no. 13 (March 7, 2013): 2676–88. http://dx.doi.org/10.1093/hmg/ddt117.

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Daigle, J., Nicholas A. Lanson, Ian Casci, John Monaghan, Charles Nichols, Dimitri Kryndushkin, Frank Shewmaker, and Udai Pandey. "Identifying dominant modifiers of mutant FUS toxicity in vivo." Molecular Neurodegeneration 8, Suppl 1 (2013): O33. http://dx.doi.org/10.1186/1750-1326-8-s1-o33.

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Hayden, Elliott, Shuzhen Chen, Abagail Chumley, Chenyi Xia, Quan Zhong, and Shulin Ju. "A Genetic Screen for Human Genes Suppressing FUS Induced Toxicity in Yeast." G3: Genes|Genomes|Genetics 10, no. 6 (April 10, 2020): 1843–52. http://dx.doi.org/10.1534/g3.120.401164.

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FUS is a nucleic acid binding protein that, when mutated, cause a subset of familial amyotrophic lateral sclerosis (ALS). Expression of FUS in yeast recapitulates several pathological features of the disease-causing mutant proteins, including nuclear to cytoplasmic translocation, formation of cytoplasmic inclusions, and cytotoxicity. Genetic screens using the yeast model of FUS have identified yeast genes and their corresponding human homologs suppressing FUS induced toxicity in yeast, neurons and animal models. To expand the search for human suppressor genes of FUS induced toxicity, we carried out a genome-scale genetic screen using a newly constructed library containing 13570 human genes cloned in an inducible yeast-expression vector. Through multiple rounds of verification, we found 37 human genes that, when overexpressed, suppress FUS induced toxicity in yeast. Human genes with DNA or RNA binding functions are overrepresented among the identified suppressor genes, supporting that perturbations of RNA metabolism is a key underlying mechanism of FUS toxicity.

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Markert, Sebastian M., Michael Skoruppa, Bin Yu, Ben Mulcahy, Mei Zhen, Shangbang Gao, Michael Sendtner, and Christian Stigloher. "Overexpression of an ALS-associated FUS mutation in C. elegans disrupts NMJ morphology and leads to defective neuromuscular transmission." Biology Open 9, no. 12 (November 4, 2020): bio055129. http://dx.doi.org/10.1242/bio.055129.

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ABSTRACTThe amyotrophic lateral sclerosis (ALS) neurodegenerative disorder has been associated with multiple genetic lesions, including mutations in the gene for fused in sarcoma (FUS), a nuclear-localized RNA/DNA-binding protein. Neuronal expression of the pathological form of FUS proteins in Caenorhabditis elegans results in mislocalization and aggregation of FUS in the cytoplasm, and leads to impairment of motility. However, the mechanisms by which the mutant FUS disrupts neuronal health and function remain unclear. Here we investigated the impact of ALS-associated FUS on motor neuron health using correlative light and electron microscopy, electron tomography, and electrophysiology. We show that ectopic expression of wild-type or ALS-associated human FUS impairs synaptic vesicle docking at neuromuscular junctions. ALS-associated FUS led to the emergence of a population of large, electron-dense, and filament-filled endosomes. Electrophysiological recording revealed reduced transmission from motor neurons to muscles. Together, these results suggest a pathological effect of ALS-causing FUS at synaptic structure and function organization.This article has an associated First Person interview with the first author of the paper.

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Martinez-Macias, Maria Isabel, Duncan AQ Moore, Ryan L. Green, Fernando Gomez-Herreros, Marcel Naumann, Andreas Hermann, Philip Van Damme, Majid Hafezparast, and Keith W. Caldecott. "FUS (fused in sarcoma) is a component of the cellular response to topoisomerase I–induced DNA breakage and transcriptional stress." Life Science Alliance 2, no. 2 (February 26, 2019): e201800222. http://dx.doi.org/10.26508/lsa.201800222.

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FUS (fused in sarcoma) plays a key role in several steps of RNA metabolism, and dominant mutations in this protein are associated with neurodegenerative diseases. Here, we show that FUS is a component of the cellular response to topoisomerase I (TOP1)–induced DNA breakage; relocalising to the nucleolus in response to RNA polymerase II (Pol II) stalling at sites of TOP1-induced DNA breaks. This relocalisation is rapid and dynamic, reversing following the removal of TOP1-induced breaks and coinciding with the recovery of global transcription. Importantly, FUS relocalisation following TOP1-induced DNA breakage is associated with increased FUS binding at sites of RNA polymerase I transcription in ribosomal DNA and reduced FUS binding at sites of RNA Pol II transcription, suggesting that FUS relocates from sites of stalled RNA Pol II either to regulate pre-mRNA processing during transcriptional stress or to modulate ribosomal RNA biogenesis. Importantly, FUS-mutant patient fibroblasts are hypersensitive to TOP1-induced DNA breakage, highlighting the possible relevance of these findings to neurodegeneration.

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Yasuda, Kyota, Huaye Zhang, David Loiselle, Timothy Haystead, Ian G. Macara, and Stavroula Mili. "The RNA-binding protein Fus directs translation of localized mRNAs in APC-RNP granules." Journal of Cell Biology 203, no. 5 (December 2, 2013): 737–46. http://dx.doi.org/10.1083/jcb.201306058.

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RNA localization pathways direct numerous mRNAs to distinct subcellular regions and affect many physiological processes. In one such pathway the tumor-suppressor protein adenomatous polyposis coli (APC) targets RNAs to cell protrusions, forming APC-containing ribonucleoprotein complexes (APC-RNPs). Here, we show that APC-RNPs associate with the RNA-binding protein Fus/TLS (fused in sarcoma/translocated in liposarcoma). Fus is not required for APC-RNP localization but is required for efficient translation of associated transcripts. Labeling of newly synthesized proteins revealed that Fus promotes translation preferentially within protrusions. Mutations in Fus cause amyotrophic lateral sclerosis (ALS) and the mutant protein forms inclusions that appear to correspond to stress granules. We show that overexpression or mutation of Fus results in formation of granules, which preferentially recruit APC-RNPs. Remarkably, these granules are not translationally silent. Instead, APC-RNP transcripts are translated within cytoplasmic Fus granules. These results unexpectedly show that translation can occur within stress-like granules. Importantly, they identify a new local function for cytoplasmic Fus with implications for ALS pathology.

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Wongworawat, Yan Chen, Yin Allison Liu, Ravi Raghavan, Charles L. White, Robin Dietz, Craig Zuppan, and Jeffrey Rosenfeld. "Aggressive FUS-Mutant Motor Neuron Disease Without Profound Spinal Cord Pathology." Journal of Neuropathology & Experimental Neurology 79, no. 4 (March 6, 2020): 365–69. http://dx.doi.org/10.1093/jnen/nlaa011.

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Abstract A 29-year-old man presented with rapidly progressive severe neck weakness, asymmetrical bilateral upper extremity weakness, bulbar dysfunction, profound muscle wasting, and weight loss. Within 1 year, his speech became unintelligible, he became gastrostomy- and tracheostomy/ventilator-dependent, and wheelchair bound. Electrophysiology suggested motor neuron disease. Whole exome sequencing revealed a heterozygous pathogenic variant in the fused in sarcoma gene (FUS), c.1574C>T,p. R525L, consistent with autosomal dominant amyotrophic lateral sclerosis. Autopsy revealed extensive denervation atrophy of skeletal musculature. Surprisingly, there was only minimal patchy depletion of motor neurons within the cervico-thoracic spinal cord anterior horn cells, and the tracts were largely preserved. TDP-43 inclusions were absent. Abnormal expression of FUS mutation product (cytoplasmic inclusions) was demonstrated by immunohistochemistry within anterior horn motor neurons. The most prominent finding was a disparity between profound neck weakness and relatively low-grade anterior horn cell loss or tract degeneration in the cervico-thoracic cord.

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De Santis, Riccardo, Vincenzo Alfano, Valeria de Turris, Alessio Colantoni, Laura Santini, Maria Giovanna Garone, Giuseppe Antonacci, et al. "Mutant FUS and ELAVL4 (HuD) Aberrant Crosstalk in Amyotrophic Lateral Sclerosis." Cell Reports 27, no. 13 (June 2019): 3818–31. http://dx.doi.org/10.1016/j.celrep.2019.05.085.

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Campanari, Maria-Letizia, Annis-Rayan Bourefis, Valerie Buee-Scherrer, and Edor Kabashi. "Freezing activity brief data from a new FUS mutant zebrafish line." Data in Brief 31 (August 2020): 105921. http://dx.doi.org/10.1016/j.dib.2020.105921.

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Bosco, Daryl A., Nathan Lemay, Hae Kyung Ko, Hongru Zhou, Chris Burke, Thomas J. Kwiatkowski, Peter Sapp, Diane McKenna-Yasek, Robert H. Brown, and Lawrence J. Hayward. "Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules." Human Molecular Genetics 19, no. 21 (August 10, 2010): 4160–75. http://dx.doi.org/10.1093/hmg/ddq335.

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Ghanbari Niaki, Amirhossein, Jaya Sarkar, Xinyi Cai, and Sua Myong. "Defective RNA Interaction Drives Aberrant Phase Separation of ALS-Linked Mutant FUS." Biophysical Journal 116, no. 3 (February 2019): 320a. http://dx.doi.org/10.1016/j.bpj.2018.11.1734.

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Yu, Yang, Shuhei Hayashi, Xianbin Cai, Chongye Fang, Wei Shi, Hiroko Tsutsui, and Jun Sheng. "Pu-Erh Tea Extract Induces the Degradation of FET Family Proteins Involved in the Pathogenesis of Amyotrophic Lateral Sclerosis." BioMed Research International 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/254680.

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FET family proteins consist of fused in sarcoma/translocated in liposarcoma (FUS/TLS), Ewing's sarcoma (EWS), and TATA-binding protein-associated factor 15 (TAF15). Mutations in the copper/zinc superoxide dismutase (SOD1), TAR DNA-binding protein 43 (TDP-43), and FET family proteins are associated with the development of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. There is currently no cure for this disease and few effective treatments are available. Epidemiological studies indicate that the consumption of tea is associated with a reduced risk of developing neurodegenerative diseases. The results of this study revealed that components of a pu-erh tea extract (PTE) interacted with FET family proteins but not with TDP-43 or SOD1. PTE induced the degradation of FET family proteins but had no effects on TDP-43 or SOD1. The most frequently occurring ALS-linked FUS/TLS mutant protein, R521C FUS/TLS, was also degraded in the presence of PTE. Furthermore, ammonium chloride, a lysosome inhibitor, but not lactacystin, a proteasome inhibitor, reduced the degradation of FUS/TLS protein by PTE. PTE significantly reduced the incorporation of R521C FUS/TLS into stress granules under stress conditions. These findings suggest that PTE may have beneficial health effects, including preventing the onset of FET family protein-associated neurodegenerative diseases and delaying the progression of ALS by inhibiting the cytoplasmic aggregation of FET family proteins.

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Kurihara, L. J., C. T. Beh, M. Latterich, R. Schekman, and M. D. Rose. "Nuclear congression and membrane fusion: two distinct events in the yeast karyogamy pathway." Journal of Cell Biology 126, no. 4 (August 15, 1994): 911–23. http://dx.doi.org/10.1083/jcb.126.4.911.

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Karyogamy is the process where haploid nuclei fuse to form a diploid nucleus during yeast mating. We devised a novel genetic screen that identified five new karyogamy (KAR) genes and three new cell fusion (FUS) genes. The kar mutants fell into two classes that represent distinct events in the yeast karyogamy pathway. Class I mutations blocked congression of the nuclei due to cytoplasmic microtubule defects. In Class II mutants, nuclear congression proceeded and the membranes of apposed nuclei were closely aligned but unfused. In vitro, Class II mutant membranes were defective in a homotypic ER/nuclear membrane fusion assay. We propose that Class II mutants define components of a novel membrane fusion complex which functions during vegetative growth and is recruited for karyogamy.

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Glomb-Reinmund, Sallie, and Margaret Kielian. "fus-1, a pH Shift Mutant of Semliki Forest Virus, Acts by Altering Spike Subunit Interactions via a Mutation in the E2 Subunit." Journal of Virology 72, no. 5 (May 1, 1998): 4281–87. http://dx.doi.org/10.1128/jvi.72.5.4281-4287.1998.

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ABSTRACT Semliki Forest virus (SFV), an enveloped alphavirus, is a well-characterized paradigm for viruses that infect cells via endocytic uptake and low-pH-triggered fusion. The SFV spike protein is composed of a dimer of E1 and E2 transmembrane subunits, which dissociate upon exposure to low pH, liberating E2 and the fusogenic E1 subunit to undergo independent conformational changes. SFV fusion and infection are blocked by agents such as ammonium chloride, which act by raising the pH in the endosome and inhibiting the low-pH-induced conformational changes in the SFV spike protein. We have previously isolated an SFV mutant, fus-1, that requires more acidic pH to trigger its fusion activity and is therefore more sensitive to inhibition by ammonium chloride. The acid shift in the fusion activity offus-1 was here shown to be due to a more acidic pH threshold for the initial dissociation of the fus-1 spike dimer, thereby resulting in a more acidic pH requirement for the subsequent conformational changes in both fus-1 E1 andfus-1 E2. Sequence analysis demonstrated that thefus-1 phenotype was due to a mutation in the E2 spike subunit, threonine 12 to isoleucine. fus-1 revertants that have regained the parental fusion phenotype and ammonium chloride sensitivity were shown to have also regained E2 threonine 12. Our results identify a region of the SFV E2 spike protein subunit that regulates the pH dependence of E1-catalyzed fusion by controlling the dissociation of the E1/E2 dimer.

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Troakes, C., T. Hortobágyi, C. Vance, S. Al-Sarraj, B. Rogelj, and C. E. Shaw. "Transportin 1 colocalization with Fused in Sarcoma (FUS) inclusions is not characteristic for amyotrophic lateral sclerosis-FUS confirming disrupted nuclear import of mutant FUS and distinguishing it from frontotemporal lobar degeneration with FUS inclusi." Neuropathology and Applied Neurobiology 39, no. 5 (July 9, 2013): 553–61. http://dx.doi.org/10.1111/j.1365-2990.2012.01300.x.

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Bursch, Franziska, Norman Kalmbach, Maximilian Naujock, Selma Staege, Reto Eggenschwiler, Masin Abo-Rady, Julia Japtok, et al. "Altered calcium dynamics and glutamate receptor properties in iPSC-derived motor neurons from ALS patients with C9orf72, FUS, SOD1 or TDP43 mutations." Human Molecular Genetics 28, no. 17 (April 22, 2019): 2835–50. http://dx.doi.org/10.1093/hmg/ddz107.

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Abstract The fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) is characterized by a profound loss of motor neurons (MNs). Until now only riluzole minimally extends life expectancy in ALS, presumably by inhibiting glutamatergic neurotransmission and calcium overload of MNs. Therefore, the aim of this study was to investigate the glutamate receptor properties and key aspects of intracellular calcium dynamics in induced pluripotent stem cell (iPSC)-derived MNs from ALS patients with C9orf72 (n = 4 cell lines), fused in sarcoma (FUS) (n = 9), superoxide dismutase 1 (SOD1) (n = 3) or transactive response DNA-binding protein 43 (TDP43) (n = 3) mutations as well as healthy (n = 7 cell lines) and isogenic controls (n = 3). Using calcium imaging, we most frequently observed spontaneous transients in mutant C9orf72 MNs. Basal intracellular calcium levels and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-induced signal amplitudes were elevated in mutant TDP43 MNs. Besides, a majority of mutant TDP43 MNs responded to 3.5-dihydroxyphenylglycine as metabotropic glutamate receptor agonist. Quantitative real-time PCR demonstrated significantly increased expression levels of AMPA and kainate receptors in mutant FUS cells compared to healthy and isogenic controls. Furthermore, the expression of kainate receptors and voltage gated calcium channels in mutant C9orf72 MNs as well as metabotropic glutamate receptors in mutant SOD1 cells was markedly elevated compared to controls. Our data of iPSC-derived MNs from familial ALS patients revealed several mutation-specific alterations in glutamate receptor properties and calcium dynamics that could play a role in ALS pathogenesis and may lead to future translational strategies with individual stratification of neuroprotective ALS treatments.

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Sleigh, James N., Andrew P. Tosolini, David Gordon, Anny Devoy, Pietro Fratta, Elizabeth M. C. Fisher, Kevin Talbot, and Giampietro Schiavo. "Mice Carrying ALS Mutant TDP-43, but Not Mutant FUS, Display In Vivo Defects in Axonal Transport of Signaling Endosomes." Cell Reports 30, no. 11 (March 2020): 3655–62. http://dx.doi.org/10.1016/j.celrep.2020.02.078.

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Devoy, Anny, Bernadett Kalmar, Michelle Stewart, Heesoon Park, Beverley Burke, Suzanna J. Noy, Yushi Redhead, et al. "Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in ‘FUSDelta14’ knockin mice." Brain 140, no. 11 (October 7, 2017): 2797–805. http://dx.doi.org/10.1093/brain/awx248.

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Vaccaro, Alexandra, Arnaud Tauffenberger, Dina Aggad, Guy Rouleau, Pierre Drapeau, and J. Alex Parker. "Mutant TDP-43 and FUS Cause Age-Dependent Paralysis and Neurodegeneration in C. elegans." PLoS ONE 7, no. 2 (February 21, 2012): e31321. http://dx.doi.org/10.1371/journal.pone.0031321.

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Nomura, Takao, Shoji Watanabe, Kumi Kaneko, Koji Yamanaka, Nobuyuki Nukina, and Yoshiaki Furukawa. "Intranuclear Aggregation of Mutant FUS/TLS as a Molecular Pathomechanism of Amyotrophic Lateral Sclerosis." Journal of Biological Chemistry 289, no. 2 (November 26, 2013): 1192–202. http://dx.doi.org/10.1074/jbc.m113.516492.

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Jin, Mengmeng, Katja Akgün, Tjalf Ziemssen, Markus Kipp, Rene Günther, and Andreas Hermann. "Interleukin-17 and Th17 Lymphocytes Directly Impair Motoneuron Survival of Wildtype and FUS-ALS Mutant Human iPSCs." International Journal of Molecular Sciences 22, no. 15 (July 27, 2021): 8042. http://dx.doi.org/10.3390/ijms22158042.

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Amyotrophic lateral sclerosis (ALS) is a progressive disease leading to the degeneration of motor neurons (MNs). Neuroinflammation is involved in the pathogenesis of ALS; however, interactions of specific immune cell types and MNs are not well studied. We recently found a shift toward T helper (Th)1/Th17 cell-mediated, pro-inflammatory immune responses in the peripheral immune system of ALS patients, which positively correlated with disease severity and progression. Whether Th17 cells or their central mediator, Interleukin-17 (IL-17), directly affects human motor neuron survival is currently unknown. Here, we evaluated the contribution of Th17 cells and IL-17 on MN degeneration using the co-culture of iPSC-derived MNs of fused in sarcoma (FUS)-ALS patients and isogenic controls with Th17 lymphocytes derived from ALS patients, healthy controls, and multiple sclerosis (MS) patients (positive control). Only Th17 cells from MS patients induced severe MN degeneration in FUS-ALS as well as in wildtype MNs. Their main effector, IL-17A, yielded in a dose-dependent decline of the viability and neurite length of MNs. Surprisingly, IL-17F did not influence MNs. Importantly, neutralizing IL-17A and anti-IL-17 receptor A treatment reverted all effects of IL-17A. Our results offer compelling evidence that Th17 cells and IL-17A do directly contribute to MN degeneration.

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De Santis, Riccardo, Laura Santini, Alessio Colantoni, Giovanna Peruzzi, Valeria de Turris, Vincenzo Alfano, Irene Bozzoni, and Alessandro Rosa. "FUS Mutant Human Motoneurons Display Altered Transcriptome and microRNA Pathways with Implications for ALS Pathogenesis." Stem Cell Reports 9, no. 5 (November 2017): 1450–62. http://dx.doi.org/10.1016/j.stemcr.2017.09.004.

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Bourefis, Annis-Rayan, Maria-Letizia Campanari, Valerie Buee-Scherrer, and Edor Kabashi. "Functional characterization of a FUS mutant zebrafish line as a novel genetic model for ALS." Neurobiology of Disease 142 (August 2020): 104935. http://dx.doi.org/10.1016/j.nbd.2020.104935.

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Takanashi, Keisuke, and Atsushi Yamaguchi. "Aggregation of ALS-linked FUS mutant sequesters RNA binding proteins and impairs RNA granules formation." Biochemical and Biophysical Research Communications 452, no. 3 (September 2014): 600–607. http://dx.doi.org/10.1016/j.bbrc.2014.08.115.

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Seagrist, John F., Shih-Heng Su, and Patrick J. Krysan. "Recombination between T-DNA insertions to cause chromosomal deletions in Arabidopsis is a rare phenomenon." PeerJ 6 (July 3, 2018): e5076. http://dx.doi.org/10.7717/peerj.5076.

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We previously described the identification of a chromosomal deletion in Arabidopsis thaliana that resulted in the elimination of genomic DNA between two T-DNA insertions located ca. 25 kilobases apart on chromosome IV. The mechanism responsible for this deletion appears to have been recombination between the closely spaced T-DNA elements located in trans in a parent plant. In our original study, we observed one such deletion event after screening ca. 2,000 seedlings using a polymerase chain reaction (PCR) assay. Because a method for precisely deleting a selected region of the Arabidopsis genome would have significant value as a research tool, we were interested in determining the frequency with which this type of T-DNA-directed deletion occurs. To do this we designed a genetic screen that would allow us to phenotypically screen for deletions caused by recombination between T-DNA inserts. This screen involved crossing T-DNA single-mutant lines in order to produce F1 plants in which the two T-DNA insertions flanked a FUSCA (FUS) locus present in the genome. Loss-of-function mutations of FUS genes cause a distinctive developmental phenotype that can be easily scored visually in young seedlings. We used T-DNA lines flanking FUS2, FUS6, FUS7, and FUS11 for this study. Recombination between the T-DNAs in an F1 parent should result in deletion of the FUS gene located between the T-DNAs. Because the deletion would be heterozygous in the F2 generation, we screened the F3 progeny of pooled F2 individuals to search for the fus loss-of-function phenotype. Using this strategy we were able to evaluate a total of 28,314 meioses for evidence of deletions caused by recombination between the T-DNA inserts. No seedlings displaying the fus phenotype were recovered, suggesting that deletions caused by recombination between T-DNA inserts are relatively rare events and may not be a useful tools for genome engineering in Arabidopsis.

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Gammie, Alison E., Valeria Brizzio, and Mark D. Rose. "Distinct Morphological Phenotypes of Cell Fusion Mutants." Molecular Biology of the Cell 9, no. 6 (June 1998): 1395–410. http://dx.doi.org/10.1091/mbc.9.6.1395.

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Cell fusion in yeast is the process by which two haploid cells fuse to form a diploid zygote. To dissect the pathway of cell fusion, we phenotypically and genetically characterized four cell fusion mutants,fus6/spa2, fus7/rvs161, fus1, and fus2. First, we examined the complete array of single and double mutants. In all cases but one, double mutants exhibited stronger cell fusion defects than single mutants. The exception was rvs161Δfus2Δ, suggesting that Rvs161p and Fus2p act in concert. Dosage suppression analysis showed that Fus1p and Fus2p act downstream or parallel to Rvs161p and Spa2p. Second, electron microscopic analysis was used to define the mutant defects in cell fusion. In wild-type prezygotes vesicles were aligned and clustered across the cell fusion zone. The vesicles were associated with regions of cell wall thinning. Analysis of Fus−zygotes indicated that Fus1p was required for the normal localization of the vesicles to the zone of cell fusion, and Spa2p facilitated their clustering. In contrast, Fus2p and Rvs161p appeared to act after vesicle positioning. These findings lead us to propose that cell fusion is mediated in part by the localized release of vesicles containing components essential for cell fusion.

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Farg, Manal A., Kai Y. Soo, Adam K. Walker, Hong Pham, Jacqueline Orian, Malcolm K. Horne, Sadaf T. Warraich, Kelly L. Williams, Ian P. Blair, and Julie D. Atkin. "Mutant FUS induces endoplasmic reticulum stress in amyotrophic lateral sclerosis and interacts with protein disulfide-isomerase." Neurobiology of Aging 33, no. 12 (December 2012): 2855–68. http://dx.doi.org/10.1016/j.neurobiolaging.2012.02.009.

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Lenzi, J., R. De Santis, V. de Turris, M. Morlando, P. Laneve, A. Calvo, V. Caliendo, A. Chio, A. Rosa, and I. Bozzoni. "ALS mutant FUS proteins are recruited into stress granules in induced pluripotent stem cell-derived motoneurons." Disease Models & Mechanisms 8, no. 7 (April 23, 2015): 755–66. http://dx.doi.org/10.1242/dmm.020099.

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Shiihashi, G., D. Ito, I. Arai, Y. Kobayashi, K. Hayashi, S. Otsuka, K. Nakajima, M. Yuzaki, S. Itohara, and N. Suzuki. "A novel ALS/FTD model mouse expressing cytoplasmic mutant FUS leads neurodegeneration via dendritic homeostasis disruption." Journal of the Neurological Sciences 381 (October 2017): 62. http://dx.doi.org/10.1016/j.jns.2017.08.231.

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Kuta, Rachel, Nancy Larochelle, Mario Fernandez, Arun Pal, Sandra Minotti, Michael Tibshirani, Kyle St. Louis, et al. "Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models." Cell Stress and Chaperones 25, no. 1 (January 2020): 173–91. http://dx.doi.org/10.1007/s12192-019-01064-1.

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AbstractUpregulation of heat shock proteins (HSPs) is an approach to treatment of neurodegenerative disorders with impaired proteostasis. Many neurons, including motor neurons affected in amyotrophic lateral sclerosis (ALS), are relatively resistant to stress-induced upregulation of HSPs. This study demonstrated that histone deacetylase (HDAC) inhibitors enable the heat shock response in cultured spinal motor neurons, in a stress-dependent manner, and can improve the efficacy of HSP-inducing drugs in murine spinal cord cultures subjected to thermal or proteotoxic stress. The effect of particular HDAC inhibitors differed with the stress paradigm. The HDAC6 (class IIb) inhibitor, tubastatin A, acted as a co-inducer of Hsp70 (HSPA1A) expression with heat shock, but not with proteotoxic stress induced by expression of mutant SOD1 linked to familial ALS. Certain HDAC class I inhibitors (the pan inhibitor, SAHA, or the HDAC1/3 inhibitor, RGFP109) were HSP co-inducers comparable to the hydroxyamine arimoclomol in response to proteotoxic stress, but not thermal stress. Regardless, stress-induced Hsp70 expression could be enhanced by combining an HDAC inhibitor with either arimoclomol or with an HSP90 inhibitor that constitutively induced HSPs. HDAC inhibition failed to induce Hsp70 in motor neurons expressing ALS-linked mutant FUS, in which the heat shock response was suppressed; yet SAHA, RGFP109, and arimoclomol did reduce loss of nuclear FUS, a disease hallmark, and HDAC inhibition rescued the DNA repair response in iPSC-derived motor neurons carrying the FUSP525Lmutation, pointing to multiple mechanisms of neuroprotection by both HDAC inhibiting drugs and arimoclomol.

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Lo Bello, Margherita, Francesca Di Fini, Antonietta Notaro, Rossella Spataro, Francesca L. Conforti, and Vincenzo La Bella. "ALS-Related Mutant FUS Protein Is Mislocalized to Cytoplasm and Is Recruited into Stress Granules of Fibroblasts from Asymptomatic FUS P525L Mutation Carriers." Neurodegenerative Diseases 17, no. 6 (2017): 292–303. http://dx.doi.org/10.1159/000480085.

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45

Kia, Azadeh, Kevin McAvoy, Karthik Krishnamurthy, Davide Trotti, and Piera Pasinelli. "Astrocytes expressing ALS-linked mutant FUS induce motor neuron death through release of tumor necrosis factor-alpha." Glia 66, no. 5 (January 30, 2018): 1016–33. http://dx.doi.org/10.1002/glia.23298.

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46

Acosta, Jamie Rae, Claire Goldsbury, Claire Winnick, Andrew P. Badrock, Stuart T. Fraser, Angela S. Laird, Thomas E. Hall, et al. "Mutant Human FUS Is Ubiquitously Mislocalized and Generates Persistent Stress Granules in Primary Cultured Transgenic Zebrafish Cells." PLoS ONE 9, no. 6 (June 9, 2014): e90572. http://dx.doi.org/10.1371/journal.pone.0090572.

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47

Scekic‐Zahirovic, Jelena, Oliver Sendscheid, Hajer El Oussini, Mélanie Jambeau, Ying Sun, Sina Mersmann, Marina Wagner, et al. "Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss." EMBO Journal 35, no. 10 (March 8, 2016): 1077–97. http://dx.doi.org/10.15252/embj.201592559.

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48

Fujii, Sakiko, Keisuke Takanashi, Keiko Kitajo, and Atsushi Yamaguchi. "Treatment with a Global Methyltransferase Inhibitor Induces the Intranuclear Aggregation of ALS-Linked FUS Mutant In Vitro." Neurochemical Research 41, no. 4 (November 24, 2015): 826–35. http://dx.doi.org/10.1007/s11064-015-1758-z.

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49

Schmid, S., R. Fuchs, M. Kielian, A. Helenius, and I. Mellman. "Acidification of endosome subpopulations in wild-type Chinese hamster ovary cells and temperature-sensitive acidification-defective mutants." Journal of Cell Biology 108, no. 4 (April 1, 1989): 1291–300. http://dx.doi.org/10.1083/jcb.108.4.1291.

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During endocytosis in Chinese hamster ovary (CHO) cells, Semliki Forest virus (SFV) passes through two distinct subpopulations of endosomes before reaching lysosomes. One subpopulation, defined by cell fractionation using free flow electrophoresis as "early endosomes," constitutes the major site of membrane and receptor recycling; while "late endosomes," an electrophoretically distinct endosome subpopulation, are involved in the delivery of endosomal content to lysosomes. In this paper, the pH-sensitive conformational changes of the SFV E1 spike glycoprotein were used to study the acidification of these defined endosome subpopulations in intact wild-type and acidification-defective CHO cells. Different virus strains were used to measure the kinetics at which internalized SFV was delivered to endosomes of pH less than or equal to 6.2 (the pH at which wild-type E1 becomes resistant to trypsin digestion) vs. endosomes of pH less than or equal to 5.3 (the threshold pH for E1 of the SFV mutant fus-1). By correlating the kinetics of acquisition of E1 trypsin resistance with the transfer of SFV among distinct endosome subpopulations defined by cell fractionation, we found that after a brief residence in vesicles of relatively neutral pH, internalized virus encountered pH less than or equal to 6.2 in early endosomes with a t1/2 of 5 min. Although a fraction of the virus reached a pH of less than or equal to 5.3 in early endosomes, most fus-1 SFV did not exhibit the acid-induced conformational change until arrival in late endosomes (t1/2 = 8-10 min). Thus, acidification of both endosome subpopulations was heterogeneous. However, passage of SFV through a less acidic early endosome subpopulation always preceded arrival in the more acidic late endosome subpopulation. In mutant CHO cells with temperature-sensitive defects in endosome acidification in vitro, acidification of both early and late endosomes was found to be impaired at the restrictive temperature (41 degrees C). The acidification defect was also found to be partially penetrant at the permissive temperature, resulting in the inability of any early endosomes in these cells to attain pH less than or equal to 5.3. In vitro studies of endosomes isolated from mutant cells suggested that the acidification defect is most likely in the proton pump itself. In one mutant, this defect resulted in increased sensitivity of the electrogenic H+ pump to fluctuations in the endosomal membrane potential.

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Trueheart, J., J. D. Boeke, and G. R. Fink. "Two genes required for cell fusion during yeast conjugation: evidence for a pheromone-induced surface protein." Molecular and Cellular Biology 7, no. 7 (July 1987): 2316–28. http://dx.doi.org/10.1128/mcb.7.7.2316.

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We characterized two genes, FUS1 and FUS2, which are required for fusion of Saccharomyces cerevisiae cells during conjugation. Mutations in these genes lead to an interruption of the mating process at a point just before cytoplasmic fusion; the partition dividing the mating pair remains undissolved several hours after the cells have initially formed a stable "prezygote." Fusion is only moderately impaired when the two parents together harbor one or two mutant fus genes, and it is severely compromised only when three or all four fus genes are inactivated. Cloning of FUS1 and FUS2 revealed that they share some functional homology; FUS1 on a high-copy number plasmid can partially suppress a fus2 mutant, and vice versa. FUS1 remains essentially unexpressed in vegetative cells, but is strongly induced by incubation of haploid cells with the appropriate mating pheromone. Immunofluorescence microscopy of alpha factor-induced a cells harboring a fus1-LACZ fusion showed the fusion protein to be localized at the cell surface, concentrated at one end of the cell (the shmoo tip). FUS1 maps near HIS4, and the intervening region (including BIK1, a gene required for nuclear fusion) was sequenced along with FUS1. The sequence of FUS1 revealed the presence of three copies of a hexamer (TGAAAC) conserved in the 5' noncoding regions of other pheromone-inducible genes. The deduced FUS1 protein sequence exhibits a striking concentration of serines and threonines at the amino terminus (46%; 33 of 71), followed by a 25-amino acid hydrophobic stretch and a predominantly hydrophilic carboxy terminus, which contains several potential N-glycosylation sites (Asn-X-Ser/Thr). This sequence suggests that FUS1 encodes a membrane-anchored glycoprotein with both N- and O-linked sugars.

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Journal articles on the topic 'Mutant FUS'

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