Control of Motoneuron Survival by Angiogenin

Kieran, Dairín; Sebastià, Jordi; Greenway, Matthew; King, Matthew; Connaughton, Dervla M.; Concannon, Caoimhín G.; Fenner, Beau J.; Hardiman, Orla; Prehn, Jochen H.M.

doi:10.1523/jneurosci.3399-08.2008

Cited by 154 publications

(195 citation statements)

References 27 publications

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“…The level of phosphorylated Akt, the activated form of Akt, is downregulated in motor neurons in autopsied spinal cords of FALS patients and SALS patients, 26 and the activation of the PI3K/Akt prosurvival pathway delays the progression of ALSlinked motor neuron death in vivo. [27][28][29] In this study, consistent with these previous observations, we found that the BTBD10 levels were decreased in the motor neurons of the spinal cords from SALS patients (Figure 5b). Although there was one ALS patient (case 5, see Table 1), whose motor neurons displayed no reduction in the BTBD10 level, the overall findings suggest that reduced expression of BTBD10 may contribute to motor neuron death in most SALS cases by downregulating the Akt-mediated prosurvival signal.…”

Section: Discussionsupporting

confidence: 92%

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: Discussionsupporting

confidence: 92%

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

et al. 2012

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“…13 What are the possible causes of acidosis during motoneuron degeneration in ALS? First, previous findings have implicated the occurrence of local hypoxia/ischemia and blood-spinal cord barrier leakage in the pathophysiology of ALS, 14 events that may lead to metabolic acidosis in the affected tissues. Reduced angiogenesis may also contribute to the pathophysiology of ALS: mutations in hypoxia inducible factor angiogenin are associated with familial and 'sporadic' forms of ALS in humans, 22 while a deletion in the hypoxia response element of the vascular endothelial growth factor (VEGF) gene is sufficient to cause motoneuron degeneration in mice.…”

Section: Discussionmentioning

confidence: 99%

“…Motoneuron survival was assessed using the trypan blue (Sigma-Aldrich, Dublin, Ireland) exclusion method and motoneuron-specific marker, smi-32, as described previously. 14,17 Following the treatment, cultures were incubated in trypan blue (Sigma-Aldrich, Dublin, Ireland) for 5 min, washed in phosphate-buffered saline (PBS) and fixed with 4% paraformaldehyde in 0.1 M PBS. Cells were immunostained with antibodies to smi-32 (1 : 500, Abcam, Cambridge, UK), for motoneuron survival counts, and the neuron-specific marker, neuronal nuclear antigen (NeuN, 1 : 400; Millipore, Cork, Ireland), for total neuronal counts.…”

Section: Discussionmentioning

confidence: 99%

“…13 Of note, mitochondrial dysfunction and Ca 2 þ overloading, as well as a local hypoxic/ischemic environment, have been implicated in the pathophysiology of ALS. [14][15][16][17] In the present study, we therefore investigated the involvement of acidotoxicity and ASIC channels in motoneuron degeneration, and explored whether pharmacological inhibition of ASIC channels represents a new approach for the treatment of ALS. …”

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Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

et al. 2013

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Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition with no cure. Mitochondrial dysfunction, Ca 2 þ overloading and local hypoxic/ischemic environments have been implicated in the pathophysiology of ALS and are conditions that may initiate metabolic acidosis in the affected tissue. We tested the hypothesis that acidotoxicity and acid-sensing ion channels (ASICs) are involved in the pathophysiology of ALS. We found that motoneurons were selectively vulnerable to acidotoxicity in vitro, and that acidotoxicity was partially reduced in asic1a-deficient motoneuron cultures. Cross-breeding of SOD1 G93A ALS mice with asic1a-deficient mice delayed the onset and progression of motor dysfunction in SOD1 mice. Interestingly, we also noted a strong increase in ASIC2 expression in motoneurons of SOD1 mice and sporadic ALS patients during disease progression. Pharmacological pan-inhibition of ASIC channels with the lipophilic amiloride derivative, 5-(N,N-dimethyl)-amiloride hydrochloride, potently protected cultured motoneurons against acidotoxicity, and, given post-symptom onset, significantly improved lifespan, motor performance and motoneuron survival in SOD1 mice. Together, our data provide strong evidence for the involvement of acidotoxicity and ASIC channels in motoneuron degeneration, and highlight the potential of ASIC inhibitors as a new treatment approach for ALS. Cell Death and Differentiation (2013) 20, 589-598; doi:10.1038/cdd.2012.158; published online 11 January 2013Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition where motoneurons in the spinal cord and brain stem die, resulting in paralysis and eventual death. Despite the significant recent advances in understanding the pathophysiology and genetics of ALS, 1 there is no cure for this condition. Currently, the only FDA-approved, disease-modifying drug used for the treatment of ALS is riluzole, which inhibits neuronal glutamate, releases and stimulates glutamate uptake into astrocytes. 2 The use of riluzole is based on the hypothesis that overactivation of Ca 2 þ -permeable AMPA receptors in motoneurons results in excitotoxicity, and that this process contributes to motoneuron death in ALS. 3 Nevertheless, the disease-modifying effects of riluzole therapy are moderate and vary among patients. 4 Acid-sensing ion channels (ASICs) represent a group of ion channels activated by protons. They belong to the epithelial sodium (Na þ ) family of amiloride-sensitive cation channels, and allow for Na þ and Ca 2 þ entry into neurons. Of the six ASIC subunits cloned, ASIC1a, ASIC2a and ASIC2b are expressed in the brain and spinal cord neurons. 5 ASIC1a and ASIC2s are found in the brain regions with high synaptic density and facilitate excitatory synaptic transmission. 6,7 ASIC1a in particular is involved in nociception and fear behavior triggered by hypercapnia. 8,9 ASICs have also been investigated as new targets for the treatment of ischemic stroke and cerebral hypoxia 10 on the premise that activation of ASIC1a during ischemia ...

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“…ANG protects mouse P19 embryonal carcinoma cells (26) and cultured mouse motor neurons from stress-induced apoptosis (27,28). Human motor neurons (hMNs) differentiated from ES cells express the motor neuron markers TUJ1, MAP2, SMI-32, and peripherin ( Fig.…”

Section: Resultsmentioning

confidence: 99%

G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments

Ivanov

O’Day

Emara

et al. 2014

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

290

270

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Angiogenin (ANG) is a stress-activated ribonuclease that promotes the survival of motor neurons. Ribonuclease inactivating point mutations are found in a subset of patients with ALS, a fatal neurodegenerative disease with no cure. We recently showed that ANG cleaves tRNA within anticodon loops to produce 5′-and 3′-fragments known as tRNA-derived, stress-induced RNAs (tiRNAs). Selected 5′-tiRNAs (e.g., tiRNA Ala , tiRNA Cys ) cooperate with the translational repressor Y-box binding protein 1 (YB-1) to displace the cap-binding complex eIF4F from capped mRNA, inhibit translation initiation, and induce the assembly of stress granules (SGs). Here, we show that translationally active tiRNAs assemble unique G-quadruplex (G4) structures that are required for translation inhibition. We show that tiRNA Ala binds the cold shock domain of YB-1 to activate these translational reprogramming events. We discovered that 5′-tiDNA Ala (the DNA equivalent of 5′-tiRNA Ala ) is a stable tiRNA analog that displaces eIF4F from capped mRNA, inhibits translation initiation, and induces the assembly of SGs. The 5′-tiDNA Ala also assembles a G4 structure that allows it to enter motor neurons spontaneously and trigger a neuroprotective response in a YB-1-dependent manner. Remarkably, the ability of 5′-tiRNA Ala to induce SG assembly is inhibited by G4 structures formed by pathological GGGGCC repeats found in C9ORF72, the most common genetic cause of ALS, suggesting that functional interactions between G4 RNAs may contribute to neurodegenerative disease.tRNA | angiogenin | stress | C9ORF72 | amyotrophic lateral sclerosis

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Control of Motoneuron Survival by Angiogenin

Cited by 154 publications

References 27 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

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments

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