FUS‐immunoreactive inclusions are a common feature in sporadic and non‐SOD1 familial amyotrophic lateral sclerosis

Deng, Han Xiang; Zhai, Hong; Bigio, Eileen H.; Yan, Jianhua; Fecto, Faisal; Ajroud, Kaouther; Mishra, Manjari; Ajroud‐Driss, Senda; Heller, Scott; Sufit, Robert; Siddique, Nailah; Mugnaini, Enrico; Siddique, Teepu

doi:10.1002/ana.22051

Cited by 290 publications

(191 citation statements)

References 33 publications

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“…The gain-of-toxic and/or loss of normal function of FUS or TDP-43 may contribute to the pathogenesis of SALS and FALS. 5,15,16 In this study, we further found that the adenoviral vector-mediated low-grade overexpression of human FUS reduced both BTBD10 expression and the Akt phosphorylation at Ser473 (which correlates with Akt activation) (Supplementary Figure S4), whereas the adenovirusmediated low-grade overexpression of TDP-43 showed a minimal tendency to reduce BTBD10 expression in some human cultured cells (Supplementary Figure S5). The overexpression of FUS by only B1.5-2-fold more than the endogenous level is enough to reduce the BTBD10 level.…”

Section: Discussionmentioning

confidence: 59%

“…Second, recent studies have shown that transgenic overexpression of FALS-linked G85R-SOD1 causes presynaptic dysfunction and a locomotion defect in C. elegans 12 and that transgenic overexpression of TAR DNA-binding protein-43 (TDP-43) or fused in sarcoma (FUS) induces both motor neuron death and a locomotion defect in C. elegans. 13,14 As TDP-43 and FUS, both of which were RNA/DNA-binding proteins, have been recently identified as major components of cytoplasmic ubiquitinated inclusion bodies in most ALS cases, including FALS and sporadic ALS (SALS) cases, and various missense mutations of TDP-43 and FUS cause FALS in an autosomal-dominant fashion, 5,15,16 it is hypothesized that the gain-of-toxic-function and/or the loss of normal function of TDP-43 or FUS is linked to motor neuron death. These results together suggest that C. elegans can be used as an animal model of human motor neuron diseases.…”

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confidence: 99%

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Reduced expression of BTBD10, an Akt activator, leads to motor neuron death

et al. 2012

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BTBD10, an Akt interactor, activates Akt by decreasing the protein phosphatase 2A-mediated dephosphorylation and inactivation of Akt. Overexpression of BTBD10 suppresses motor neuron death that is induced by a familial amyotrophic lateral sclerosis (ALS)-linked superoxide dismutase 1 (SOD1) mutant, G93A-SOD1 in vitro. In this study, we further investigated the BTBD10-mediated suppression of motor neuron death. We found that the small interfering RNA-mediated inhibition of BTBD10 expression led to the death of cultured motor neurons. In Caenorhabditis elegans (C. elegans), disruption of the btbd-10 gene caused not only loss of neurons, including both motor and touch-receptor neurons, but also a locomotion defect. In addition, we found that the expression of BTBD10 was generally decreased in the motor neurons from patients of sporadic ALS and transgenic mice overexpressing G93A-SOD1 (G93A-SOD1-transgenic mice). Collectively, these results suggest that the reduced expression of BTBD10 leads to motor neuron death both in vitro and in vivo. A gain-of-toxic-function of an intracellular molecule or a loss of normal function of an essential intracellular molecule, including an intracellular prosurvival signal, contributes to cell death. The Akt family of proteins (Akt1, 2 and 3 in mammalian cells) provides a major intracellular prosurvival signal by phosphorylating many target proteins. 1 The major upstream activator of Akt is the phosphatidylinositol 3-kinase (PI3K)-mediated signal that activates Akt by phosphorylation. Akt's activity is also regulated by protein phosphatase-mediated dephosphorylation. 2 In our previous study, we showed that BTBD10 activates Akt by inhibiting protein phosphatase 2A (PP2A)-mediated Akt dephosphorylation. 3 Recent advances in genetics and neuroscience have suggested that both gains of toxic and/or losses of normal function of intracellular molecules contribute to the pathogenesis of neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a representative motor neuron-specific neurodegenerative disease. 4 Approximately 10% of ALS cases are genetically inherited. 4,5 Dominant mutations in the superoxide dismutase 1 (SOD1) gene (the first identified familial ALS (FALS)-linked gene) account for approximately 20% of FALS cases. The gain-of-toxic-function of SOD1, caused by a FALS-linked mutation, is thought to be closely linked to the ALS pathogenesis. The second identified FALS-linked gene, a FALS-linked mutation of which results in an autosomal-recessive phenotype, encodes a protein named alsin. 6,7 Loss of alsin function, caused by a FALSlinked mutation, leads to the abnormal endolysosomal trafficking and contributes to motor neuron death. 8 We have independently shown that wild-type alsin suppresses mutant SOD1-induced neuronal cell death by activating a prosurvival pathway involving Rac1, PI3K and Akt3, and that FALS-linked mutations in the gene abolish the alsin function. 9,10 To further characterize the Akt-mediated prosurvival pathways that are linked to the ALS pathogenesi...

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Section: Discussionmentioning

confidence: 59%

mentioning

confidence: 99%

Reduced expression of BTBD10, an Akt activator, leads to motor neuron death

et al. 2012

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“…The "ALS pathway" described in the KEGG database (www.genome.jp/kegg/pathway/hsa/hsa05014. html) does not currently include recent discoveries, including key processes such as mRNA metabolism (53,54). We therefore generated an "ALS network" by creating a list of proteins found in inclusions, data from supersaturation scores, connectivity network analysis, and existing KEGG pathways (ALS, regulation of autophagy, glutamatergic synapse, RNA transport, mRNA surveillance pathway, transcription factors, ubiquitin-mediated proteolysis, and protein processing in the endoplasmic reticulum; www.genome.jp/ kegg/pathway.html), and used this list to construct a new model for functional disruption in ALS (Fig.…”

Section: Coaggregators Are More Supersaturated Than Native Interactormentioning

confidence: 99%

Spinal motor neuron protein supersaturation patterns are associated with inclusion body formation in ALS

Ciryam

Lambert-Smith

Bean

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Amyotrophic lateral sclerosis (ALS) is a heterogeneous degenerative motor neuron disease linked to numerous genetic mutations in apparently unrelated proteins. These proteins, including SOD1, TDP-43, and FUS, are highly aggregation-prone and form a variety of intracellular inclusion bodies that are characteristic of different neuropathological subtypes of the disease. Contained within these inclusions are a variety of proteins that do not share obvious characteristics other than coaggregation. However, recent evidence from other neurodegenerative disorders suggests that diseaseaffected biochemical pathways can be characterized by the presence of proteins that are supersaturated, with cellular concentrations significantly greater than their solubilities. Here, we show that the proteins that form inclusions of mutant SOD1, TDP-43, and FUS are not merely a subset of the native interaction partners of these three proteins, which are themselves supersaturated. To explain the presence of coaggregating proteins in inclusions in the brain and spinal cord, we observe that they have an average supersaturation even greater than the average supersaturation of the native interaction partners in motor neurons, but not when scores are generated from an average of other human tissues. These results suggest that inclusion bodies in various forms of ALS result from a set of proteins that are metastable in motor neurons, and thus prone to aggregation upon a disease-related progressive collapse of protein homeostasis in this specific setting.protein aggregation | protein misfolding | protein homeostasis | supersaturation | motor neuron disease

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“…Motor neuron degeneration is associated primarily with the pathological aggregation of ubiquitin, fused in sarcoma protein, and the transactive response DNA binding protein (TAR) DNAbinding protein of 43-kDa in the cytoplasm of motor neuron cell bodies [114,115]. In addition, ALS has also been associated with an important impairment of energy metabolism [116].…”

Section: Alsmentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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FUS‐immunoreactive inclusions are a common feature in sporadic and non‐SOD1 familial amyotrophic lateral sclerosis

Cited by 290 publications

References 33 publications

Reduced expression of BTBD10, an Akt activator, leads to motor neuron death

Reduced expression of BTBD10, an Akt activator, leads to motor neuron death

Spinal motor neuron protein supersaturation patterns are associated with inclusion body formation in ALS

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

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