Greenway, M. J. et al. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nature Genet. 38, 411-413

Umeå University, Umeå, Västerbotten, Sweden
Nature Genetics (Impact Factor: 29.35). 05/2006; 38(4):411-3. DOI: 10.1038/ng1742
Source: PubMed


We recently identified angiogenin (ANG) as a candidate susceptibility gene for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by adult-onset loss of motor neurons. We now report the finding of seven missense mutations in 15 individuals, of whom four had familial ALS and 11 apparently 'sporadic' ALS. Our findings provide further evidence that variations in hypoxia-inducible genes have an important role in motor neuron degeneration.

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    • "Although FUS represents an ALS gene, an accumulation of FUS protein in inclusion bodies in neuronal cytoplasm and nucleus was associated with clinicopathological subtypes of FTD (Mackenzie et al., 2010). Mutations in other genes involved in the pathogenesis of ALS also include senataxin (SETX) (Chen et al., 2004), angiogenin (ANG) (Greenway et al., 2006), and Ataxin-2 (Elden et al., 2010; Van Damme et al., 2011). "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is now recognized as a multisystem disorder, in which the primary pathology is the degeneration of motor neurons, with cognitive and/or behavioral dysfunctions that constitutes the non-motor manifestations of ALS. The combination of clinical, neuroimaging, and neuropathological data, and detailed genetic studies suggest that ALS and frontotemporal dementia (FTD) might form part of a disease continuum, with pure ALS and pure FTD at the two extremes. Mutations in the superoxide dismutase 1 (SOD1) gene were the first genetic mutations linked to the insurgence of ALS. Since that discovery numerous animal models carrying SOD1 mutations have been created. Despite their limitations these animal models, particularly the mice, have broaden our knowledge on the system alterations occurring in the ALS spectrum of disorders. The present review aims at providing an overview of the data obtained with the SOD1 animal models first and foremost on the cortical and subcortical regions, the cortico-striatal and hippocampal synaptic plasticity, dendritic branching and glutamate receptors function.
    Full-text · Article · Nov 2015 · Neuroscience & Biobehavioral Reviews
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    • "Amyotrophic lateral sclerosis (ALS) involves the slowly progressive dysfunction and degeneration of the motor neurons in the brainstem nuclei, corticospinal tract, and ventral roots of the spinal cord and generally occurs after the age of 40 years (Evans et al., 2013; Garbuzova- Davis et al., 2007). It has a familial and sporadic etiology, wherein mutations in one of more than 12 genes are thought to cause ALS (Greenway et al., 2006; Su et al., 2014). At the subcellular level, the mitochondrial cristae in the ECs and neuropil are disorganized and degenerative . "
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    ABSTRACT: Abstract Brain microcirculation plays an important role in the pathogenesis of various brain diseases. Several specific features of the circulation in the brain and its functions deserve special attention. The brain is extremely sensitive to hypoxia, and brain edema is more dangerous than edema in other tissues. Brain vessels are part of the blood-brain barrier, which prevents the penetration of some of the substances in the blood into the brain tissue. Herein, we review the processes of angiogenesis and the changes that occur in the brain microcirculation in the most prevalent neurodegenerative diseases. There are no uniform vascular changes in the neurodegenerative diseases. In some cases, the vascular changes are secondary consequences of the pathological process, but they could also be involved in the pathogenesis of the primary disease and contribute to the degeneration of neurons, based on their quantitative characteristics. Additionally, we described the stereological methods that are most commonly used for generating qualitative and quantitative data to assess changes in the microvascular bed of the brain.
    Full-text · Article · Oct 2014 · Reviews in the neurosciences
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    • "Similarly , loss - of - function of the kinase CLP1 causes neurological diseases in mouse and human due to aberrant accumulation of tRNA fragments caused by impaired pre - tRNA processing and increased cell sensitivity to oxida - tive stress ( Hanada et al , 2013 ; Schaffer et al , 2014 ; Karaca et al , 2014 ) . Loss - of - function mutations in angiogenin have also been associ - ated with neurological diseases , supporting the hypothesis is that angiogenin rather exerts a neuro - protective role ( Greenway et al , 2006 ; Steidinger et al , 2011 ) . Our data challenge this view because inhibition of angiogenin in the absence of tRNA methylation promotes cellular survival . "
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    ABSTRACT: Mutations in the cytosine-5 RNA methyltransferase NSun2 cause microcephaly and other neurological abnormalities in mice and human. How post-transcriptional methylation contributes to the human disease is currently unknown. By comparing gene expression data with global cytosine-5 RNA methylomes in patient fibroblasts and NSun2-deficient mice, we find that loss of cytosine-5 RNA methylation increases the angiogenin-mediated endonucleolytic cleavage of transfer RNAs (tRNA) leading to an accumulation of 5′ tRNA-derived small RNA fragments. Accumulation of 5′ tRNA fragments in the absence of NSun2 reduces protein translation rates and activates stress pathways leading to reduced cell size and increased apoptosis of cortical, hippocampal and striatal neurons. Mechanistically, we demonstrate that angiogenin binds with higher affinity to tRNAs lacking site-specific NSun2-mediated methylation and that the presence of 5′ tRNA fragments is sufficient and required to trigger cellular stress responses. Furthermore, the enhanced sensitivity of NSun2-deficient brains to oxidative stress can be rescued through inhibition of angiogenin during embryogenesis. In conclusion, failure in NSun2-mediated tRNA methylation contributes to human diseases via stress-induced RNA cleavage.
    Full-text · Article · Jul 2014 · The EMBO Journal
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