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ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis

Umeå University, Umeå, Västerbotten, Sweden
Nature Genetics (Impact Factor: 29.65). 05/2006; 38(4):411-3. DOI: 10.1038/ng1742
Source: PubMed

ABSTRACT 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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    • "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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    Reviews in the neurosciences 10/2014; 26(1). DOI:10.1515/revneuro-2014-0049 · 3.31 Impact Factor
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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.
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    • "The causes of the vast majority of cases of ALS remain elusive but approximately 10% are familial ALS (FALS), indicating that genetic components are important in the pathogenesis . To date, mutations in at least 30 genes have been implicated in ALS (Sreedharan and Brown, 2013), and approximately a half of the genes are associated with dominantly inherited FALS, including SOD1 (Rosen, 1993), Senataxin (Chen et al., 2004), FUS (Kwiatkowski et al., 2009; Vance et al., 2009), VAPB (Nishimura et al., 2004), ANG (Greenway et al., 2006), TARDBP (Sreedharan et al., 2008), FIG4 (Chow et al., 2009), DAO (Mitchell et al., 2010), OPTN (Maruyama et al., 2010), ATXN2 (Elden et al., 2010), VCP (Johnson et al., 2010), C9ORF72 (DeJesus-Hernandez et al., 2011; Renton et al., 2011), UBQLN2 (Deng et al., 2011), SQSTM1 (Fecto et al., 2011), PFN1 (Wu et al., 2012), HNRNPA1 (Kim et al., 2013), and ERBB4 (Takahashi et al., 2013). Among them, only mutations in SOD1, FUS, TARDBP, and C9ORF72 genes account for a significant number of ALS cases. "
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