ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis
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.
- SourceAvailable from: Zbynek Tonar
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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 . "
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.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 . "
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.The EMBO Journal 07/2014; 33(18). DOI:10.15252/embj.201489282 · 10.75 Impact Factor
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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. "
ABSTRACT: Identification of genetic mutations has been of burgeoning importance in amyotrophic lateral sclerosis (ALS) in recent years. The aim of this study was to determine the frequency and spectrum of mutations in major ALS-causing genes in a Taiwanese ALS cohort of Han Chinese origin. Mutational analyses of the SOD1, TARDBP, FUS, OPTN, VCP, UBQLN2, SQSTM1, PFN1, HNRNPA1, and HNRNPA2B1 genes were carried out by direct sequencing in 161 unrelated patients with ALS, including 30 with familial ALS (FALS) and 131 with sporadic ALS (SALS). The CAG repeat size in ATXN2 and the GGGGCC repeat expansion in C9ORF72 of the patients were also investigated. Mutations were identified in 33 patients (20.5%, 33/161), including 22 with FALS and 11 with SALS. Mutations were identified most frequently in SOD1 (7.5%). Three mutations are novel, including SOD1 p.G10A, SOD1 p.D83N, and OPTN p.L494W. These findings broaden the spectrum of ALS-causing mutations and are indispensable for designing optimal strategies of mutational analysis and genetic counseling of ALS for patients of Chinese origin.Neurobiology of Aging 05/2014; 35(10). DOI:10.1016/j.neurobiolaging.2014.05.008 · 4.85 Impact Factor