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

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.

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

“…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.…”

Second-order effects plus pan-European political swings: An analysis of European Parliament elections across time

“…Moreover, recent studies have suggested that angiogenin is an important neurodevelopmental protein with neuroprotective properties, and that mutant ANG impairs neurite outgrowth. [2][3][4].…”

Genetics of Familial Amyotrophic Lateral Sclerosis

“…The ribonuclease A activity has been shown to be reduced or lost in ANG mutant proteins. ANG is a potent inducer of neovascularization in vivo and has been shown to play a key role in neurite outgrowth and pathfinding during early embryonic development (Subramanian et al 2008). Its structure and function are partially homologous to that of vascular endothelial cell growth factor (VEGF); a previously reported genetic susceptibility and disease modifying factor in the development of neurodegeneration (Lambrechts et al 2009), and both VEGF and ANG have been shown to be neuroprotective.…”