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Human angiogenin is a neuroprotective factor and amyotrophic lateral sclerosis associated angiogenin variants affect neurite extension/pathfinding and survival of motor neurons

Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK.
Human Molecular Genetics (Impact Factor: 6.68). 02/2008; 17(1):130-49. DOI: 10.1093/hmg/ddm290
Source: PubMed

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a late onset neurodegenerative disorder affecting upper and lower motor neurons (MNs). The molecular mechanisms underlying ALS are poorly understood. Mutations in SOD1 is one of the known causes of ALS but occur only in a very small number of cases of ALS. Interestingly, mutations in human angiogenin (hANG), a member of the ribonuclease A (RNase A) superfamily known to be involved in neovascularization, have been recently reported in patients with ALS, but the effects of these mutations on MN differentiation and survival has not been investigated. We have used the well-characterized pluripotent P19 embryonal carcinoma (EC) cell culture model of neuro-ectodermal differentiation to study the effects of hANG-ALS variants on MN differentiation and survival. Here we report that P19 EC cells induced to differentiate in the presence of hANG and hANG-ALS-associated variants internalize the wild-type and variant proteins. The P19 EC cells differentiate to form neurons but the ability of the neurites to extend and make contacts with neighbouring neurites is compromised when treated with the hANG-ALS variants. In addition, hANG-ALS variants also have a cytotoxic effect on MNs leading to their degeneration. hANG was able to protect neurons from hypoxia-induced cell death, but the variants of hANG implicated in ALS lacked the neuroprotective activity. Our findings show that ANG plays an important role in neurite extension/pathfinding and survival providing a causal link between mutations in hANG and ALS.

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    • "Additional mutations in ANG have been identified in various populations with ALS (Wu et al. 2007; Conforti et al. 2008; Gellera et al. 2008; Paubel et al. 2008). Similar to activities described above for ALS2/alsin, cell culture studies have shown that mutant forms of human ANG impeded neurite extension and promoted degeneration (Subramanian et al. 2008). ANG promotes survival of motor neurons in vitro and in vivo and angiogenin delivery to SOD1 (G93A) mice increased lifespan and motor neuron survival (Kieran et al. 2008). "
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    • " , 2010 ) , and acts predominantly in hypoxic and proinflammatory conditions ( Mor et al . , 2004 ; Wang et al . , 2009 ; Yoshida et al . , 2010 ) , while angiogenin is a physiologically occurring proangiogenic factor ( Komolova and Ionova , 2010 ) with anti - inflammatory capabilities ( Tschesche et al . , 1994 ) , protective effects on neurons ( Subramanian et al . , 2008 ) and stimulatory action on prostacyclin and NO synthesis ( Bicknell and Vallee , 1989 ; Trouillon et al . , 2010 ) . All these angiogenin effects are very impotent for the proper function of the retina . Notably antiinflammatory action seems to be beneficial for diabetic patients , as inflammation is the main factor involved in pathoge"
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    • "). Angiogenin is a member of the ribonuclease A (RNase) superfamily. It protects motor neurons from hypoxic death in vitro (Subramanian et al., 2008; Sebastia et al., 2009) and administration of angiogenin to mutant SOD1 mice increased their life span (Kieran et al., 2008). The mutations identified affect the protective effect of angiogenin but it is unknown whether this loss-of-function is of relevance to the in vivo effect in motor neuron degeneration. "
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