Human Molecular Genetics Advance Access originally published online on October 4, 2007
Human Molecular Genetics 2008 17(1):130-149; doi:10.1093/hmg/ddm290
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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
* To whom correspondence should be addressed at: Department of Biology and Biochemistry, Building 4 South, University of Bath, Claverton Down, Bath BA2 7AY, UK. Tel: +44 1225386315; Fax: +44 1225386779; Email bssvss{at}bath.ac.uk
Received August 14, 2007; Accepted September 30, 2007
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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Kulka, N. Fukuishi, and D. D. Metcalfe Human mast cells synthesize and release angiogenin, a member of the ribonuclease A (RNase A) superfamily J. Leukoc. Biol., November 1, 2009; 86(5): 1217 - 1226. [Abstract] [Full Text] [PDF]
|
|