Another angiogenic gene linked to amyotrophic lateral sclerosis

University of Leuven, Louvain, Flanders, Belgium
Trends in Molecular Medicine (Impact Factor: 9.45). 09/2006; 12(8):345-7. DOI: 10.1016/j.molmed.2006.06.008
Source: PubMed


A new study by Greenway and colleagues links mutations in the angiogenin gene to patients with amyotrophic lateral sclerosis (ALS)--a progressive and fatal motoneuron disease. This is an unexpected finding because angiogenin was originally identified as a molecule involved in the formation of blood vessels (angiogenesis). Angiogenin bears striking similarity to vascular endothelial growth factor (VEGF), which is the prototypic angiogenic factor that has recently emerged as a molecule with important neuroprotective activities. Besides VEGF, angiogenin is the second so-called angiogenic factor implicated in ALS, raising the question of whether additional angiogenic factors might have a role in ALS. Overall, these findings identify angiogenin as a novel candidate gene in the pathogenesis of ALS--a discovery that ultimately might lead to the development of new therapeutic strategies.

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Available from: Peggy Lafuste
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    • "The expression of this VEGF is dependent on the nucleolar ANG which directly helps in stimulating the proliferation of epithelial cells and helps in angiogenesis [17]. However, this hypothesis raises a question whether angiogenin crosses the blood brain barrier or is retained in cerebrospinal fluid [18]. "
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    ABSTRACT: Oxidative stress and angiogenic factors have been placed as the prime focus of scientific investigations after an establishment of link between vascular endothelial growth factor promoter (VEGF), hypoxia, and amyotrophic lateral sclerosis (ALS) pathogenesis. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter and mutant superoxide dismutase 1 (SOD1) which are characterised by atrophy and muscle weakness resulted in phenotype resembling human ALS in mice. This results in lower motor neurodegeneration thus establishing an important link between motor neuron degeneration, vasculature, and angiogenic molecules. In this review, we have presented human, animal, and in vitro studies which suggest that molecules like VEGF have a therapeutic, diagnostic, and prognostic potential in ALS. Involvement of vascular growth factors and hypoxia response elements also highlights the converging role of oxidative stress and neurovascular network for understanding and treatment of various neurodegenerative disorders like ALS.
    Full-text · Article · Dec 2013 · Oxidative Medicine and Cellular Longevity
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    • "The potent angiogenic factor, angiogenin, has recently been associated with neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS) and Parkinson Disease (PD) [1], [2]. Angiogenin was first linked to ALS through genetic studies that revealed the association of certain angiogenin mutations with both sporadic and familial forms of ALS [1], [2], [3], [4], [5], [6], [7], [8], [9]. Wildtype angiogenin has been shown to reduce motoneuron cell death in response to hypoxia, serum deprivation, ER stress, and excitotoxicity, while mutant forms of angiogenin associated with ALS fail to reduce toxicity in these models [10], [11], [12]. "
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    ABSTRACT: The angiogenic factor, angiogenin, has been recently linked to both Amyotrophic Lateral Sclerosis (ALS) and Parkinson Disease (PD). We have recently shown that endogenous angiogenin levels are dramatically reduced in an alpha-synuclein mouse model of PD and that exogenous angiogenin protects against cell loss in neurotoxin-based cellular models of PD. Here, we extend our studies to examine whether activation of the prosurvival Akt pathway is required for angiogenin's neuroprotective effects against 1-methyl-4-phenylpyridinium (MPP+), as observed in ALS models, and to test the effect of virally-mediated overexpression of angiogenin in an in vivo PD model. Using a dominant negative Akt construct, we demonstrate that inhibition of the Akt pathway does not reduce the protective effect of angiogenin against MPP+ toxicity in the dopaminergic SH-SY5Y cell line. Furthermore, an ALS-associated mutant of angiogenin, K40I, which fails to induce Akt phosphorylation, was similar to wildtype angiogenin in protection against MPP+. These results confirm previous work showing neuroprotective effects of angiogenin against MPP+, and indicate that Akt is not required for this protective effect. We also investigated whether adeno-associated viral serotype 2 (AAV2)-mediated overexpression of angiogenin protects against dopaminergic neuron loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. We found that angiogenin overexpression using this approach does not reduce the MPTP-induced degeneration of dopaminergic cells in the substantia nigra, nor limit the depletion of dopamine and its metabolites in the striatum. Together, these findings extend the evidence for protective effects of angiogenin in vitro, but also suggest that further study of in vivo models is required to translate these effects into meaningful therapies.
    Full-text · Article · Feb 2013 · PLoS ONE
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    • "Neurovascular molecules seem to establish another mechanism in ALS (VEGF, angiogenin) and related diseases (e.g. progranulin in FTLD; Lambrechts et al., 2006). The involvement of ER stress is yet another one (SOD1, VAPB and others; Kanekura et al., 2009). "
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    ABSTRACT: Amyotrophic lateral sclerosis is a degenerative disease affecting the motor neurons. In spite of our growing insights into its biology, it remains a lethal condition. The identification of the cause of several of the familial forms of ALS allowed generation of models to study this disease both in vitro and in vivo. Here, we summarize what is known about the pathogenic mechanisms of ALS induced by hereditary mutations, and attempt to identify the relevance of these findings for understanding the pathogenic mechanisms of the sporadic form of this disease.
    Full-text · Article · Jun 2010 · European Journal of Neuroscience
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