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Immunohistochemistry of sporadic amyotrophic lateral sclerosis (SALS) case with p.K54E ANG mutation. Images show p62 (a–d), TDP-43 (e–g), FUS (h), angiogenin (i), H&E (j), CD68 (k) and α2 actinin (l) showing: neuronal (a, b, d, e and g) and glial (c and f) cytoplasmic inclusions in the spinal cord; neuronal cytoplasmic inclusions in the motor cortex (d and g); normal, predominantly nuclear labelling of FUS in the spinal cord (h), granular cytoplasmic staining in a motor neurone with the appearance of lipofuscin (i); Bunina bodies (arrowheads; j); a microglial reaction that is most marked in the lateral descending tract of the spinal cord and least marked in the dorsal columns (k); normal labelling of Z-disc in skeletal muscle by α2 actinin (l). Scale: a–i and l, bar = 20 μm; j, bar = 20 μm; k, bar = 1 mm.
Source publication
Aims
Five to 10% of cases of amyotrophic lateral sclerosis are familial, with the most common genetic causes being mutations in the C9ORF72, SOD1, TARDBP and FUS genes. Mutations in the angiogenin gene, ANG, have been identified in both familial and sporadic patients in several populations within Europe and North America. The aim of this study was...
Citations
... Angiogenin, encoded by the hypoxia-inducible gene ANG, is a member of the pancreatic ribonuclease superfamily [293] and, as well as angiogenesis, is also involved in ribosomal biogenesis [294,295]. Defects in this protein are associated with the impairment of its nuclear localization and diminished ribonucleolytic activity [295] (Figure 3), both of which are essential for normal ANG functioning and motor neuron viability. ...
... Angiogenin, encoded by the hypoxia-inducible gene ANG, is a member of the pancreatic ribonuclease superfamily [293] and, as well as angiogenesis, is also involved in ribosomal biogenesis [294,295]. Defects in this protein are associated with the impairment of its nuclear localization and diminished ribonucleolytic activity [295] (Figure 3), both of which are essential for normal ANG functioning and motor neuron viability. ...
Amyotrophic lateral sclerosis (ALS) is a terminal late-onset condition characterized by the loss of upper and lower motor neurons. Mutations in more than 30 genes are associated to the disease, but these explain only~20% of cases. The molecular functions of these genes implicate a wide range of cellular processes in ALS pathology, a cohesive understanding of which may provide clues to common molecular mechanisms across both familial (inherited) and sporadic cases and could be key to the development of effective therapeutic approaches. Here, the different pathways that have been investigated in ALS are summarized, discussing in detail: mitochondrial dysfunction, oxidative stress, axonal transport dysregulation, glutamate excitotoxicity, endosomal and vesicular transport impairment, impaired protein homeostasis, and aberrant RNA metabolism. This review considers the mechanistic roles of ALS-associated genes in pathology, viewed through the prism of shared molecular pathways.
... 98 While it is not known if mutations in ANG or RNASE4 are present in AD+P, some of these mutations result in tar DNA binding protein 43 (TDP43) inclusion pathology on postmortem exam in ALS/FTD patients. 99 We have previously reported that the presence of comorbid TDP43 pathology in AD is independently associated with psychosis risk. 100 We previously identified, and independently replicated, an inverse association between polygenic risk for schizophrenia, defined by a limited set of schizophrenia risk SNPs 69 , and risk for psychosis in AD. 28 It was thus somewhat surprising that we saw a non-significant genetic correlation between these two disorders when considering both a larger set of SNPs and a substantially enlarged cohort of AD subjects with and without psychosis. ...
Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD+P), affecting ~ 40% to 60% of individuals with AD. AD+P identifies a subgroup of AD patients with poor outcomes. The strongest clinical predictor of AD+P is a greater degree of cognitive impairment than in AD subjects without psychosis (AD-P). Other frequently replicated correlates of AD+P include elevated depressive symptoms. Although the estimated heritability of psychosis in AD is 61%, the underlying genetic sources of this risk are not known. We report a genome-wide meta-analysis of 12,317 AD subjects, with and without psychosis. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in the gene ENPP6 (best SNP rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p=1.26x10-8) and one spanning the 3-prime-UTR of an alternatively spliced transcript of SUMF1 (best SNP rs201109606, O.R. 0.65 (0.56-0.76), p=3.24x10-8), had genome-wide significant associations with the risk of psychosis in AD. Psychosis risk in AD demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We had previously observed a negative genetic correlation with schizophrenia, instead we now found a stronger negative correlation with the related phenotype of bipolar disorder. Psychosis risk in AD was not genetically correlated with AD or other neurodegenerative diseases. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture. Study of the genetic mechanisms underlying the associations of loci in ENPP6 and SUMF1 with psychosis in AD are warranted.
... Blocks were then embedded in paraffin wax, sectioned and stained for haematoxylin and eosin. Immunohistochemistry (IHC) for phosphorylated TDP-43, tau, CD68, TBK1 and IRF3 was performed ( Table 1) using standard protocols (27,28). Immunohistochemistry for TBK1 and IRF3 was performed in 3 neurologically normal controls and 3 sporadic MND cases in addition to Case 2. ...
Aims:
Mutations in TANK binding kinase gene (TBK1) are causative in amyotrophic lateral sclerosis (ALS), however correlations between clinical features and TBK1 mutations have not been fully elucidated. We aimed to identify and compare TBK1 mutations to clinical features in a cohort of ALS patients from Northern England.
Methods:
TBK1 mutations were analysed in 290 ALS cases. Immunohistochemistry was performed in brain and spinal cord of one case with a novel in-frame deletion.
Results:
Seven TBK1 variants were identified, including one novel in-frame deletion (p.85delIle). In silico analysis and literature suggested four variants were pathogenic, and three were variants of uncertain significance or benign. Post-mortem immunohistochemistry established an individual with the novel in-frame deletion had classical ALS and Type B FTLD-TDP pathology, with no changes in TBK1 staining or interferon regulatory factor IRF3.
Conclusions:
TBK1 mutations were present in 1.38% of our cohort, and screening showed no clear genotype-phenotype associations compared to other genetic and sporadic ALS cases. TBK1 immunohistochemistry was consistent with previously published literature and we are the first to show no differential expression of interferon regulatory factor IRF3, a downstream effector of TBK1 in the immune pathway, in the TBK1-mutant tissue, compared to controls.
... [21][22][23][24] On the other hand, although no BBs are detected in cases with optineurin mutations, fALS-related mutations of angiogenin, TDP-43, valosin-containing protein and chromosome 9 open reading frame 72 cause the occurrence of TDP-43-IR inclusions along with BBs (summarized in Table 1). 23,[25][26][27][28][29] Moreover, Kimura et al. reported colocalization of BBs and p-TDP-43-IR inclusions not only in the lower motor neurons but in the non-motor neurons in the oculomotor nucleus, medullary reticular formation and cerebellar dentate nucleus in an ALS patient after long-term survival. 30 Thus, BBs do not occur in cases without TDP-43-IR inclusions. ...
Sporadic amyotrophic lateral sclerosis (sALS) is characterized pathologically by loss of upper and lower motor neurons with occurrence of transactivation response DNA‐binding protein 43 kDa (TDP‐43)‐immunoreactive skein‐like and round hyaline inclusions. Lewy body‐like hyaline inclusions (LBHIs) are also found in a small proportion of sALS cases as well as in individuals with familial ALS with mutations in the Cu/Zu superoxide dismutase (SOD1) gene. LBHIs in sALS are immunopositive for TDP‐43, but not for SOD1. The occurrence of Bunina bodies (BBs) is another key pathological feature of sALS. BBs are immunonegative for TDP‐43 but immunopositive for cystatin C, transferrin, peripherin and sortilin‐related receptor CNS expressed 2 (SorCS2). Despite differences between BBs and TDP‐43 inclusions in terms of protein constituents and ultrastructure, the two inclusions are known to be linked. We recently encountered a case of sALS of 10 months duration in which many round hyaline inclusions, LBHIs and BBs were found in the anterior horn cells of the spinal cord. Our immunohistochemical and ultrastructural examinations revealed the presence of BBs within the skein‐like and round hyaline inclusions, and in the LBHIs. Colocalization of BB‐related proteins (cystatin C, transferrin and SorCS2) and TDP‐43 was also confirmed in the halo of LBHIs as well as in the marginal portion of the skein‐like and round hyaline inclusions. These findings suggest that there is some relationship between BBs and TDP‐43‐immunoreactive inclusions in terms of their formation processes.
... In a recently reported cohort of 516 cases only one case of sporadic ALS with mutation in ANG was identified (p.K54E). 43 Neuropathology demonstrated neuronal and glial cytoplasmic inclusions staining positively for p62 and TDP-43, indistinguishable from sporadic ALS. No abnormal distribution of angiogenin protein was observed. ...
... Quite a few variants of ANG in patients with ALS have been reported [2,[4][5][6][7][8][9][10][11][12][13][14][15][16][17], among which the K17I and I46V variants have been studied most extensively and have been identified in patients of Caucasians origin but not in those of Japanese [18] and Korean [19]. Current studies suggested lack of association between I46V variant frequency and ALS susceptibility [2,[7][8][9][10]. ...
... A total of 497 potentially eligible articles were identified after searching databases and review of the selected reference lists, and 298 were retained after removing duplicates. After eliminating 279 articles based on the title and abstract, the remaining 19 were read in full and 14 were excluded because the frequency of the ANG K17I variant was zero in both cases and controls [18,19,24], because the authors did not examine the possible correlation between the ANG K17I variants and ALS risk [9][10][11][12][13][14][15][16], because the study applies neither case-control nor genomewide association design [20,25], or because the study [2] involved a population that overlapped with that in a larger study [4] that was included in the meta-analysis. ...
The study purpose is to perform a meta-analysis to help resolve the debate of whether the Angiogenin (ANG) K17I variant is associated with amyotrophic lateral sclerosis (ALS) risk in Caucasian. Three literature databases were searched for eligible studies published up to January 8, 2015: PubMed, Embase and Web of Science using the following search terms: amyotrophic lateral sclerosis or ALS and Angiogenin or ANG. Five eligible articles were identified, which reported 6 case-control studies and a total of 2326 cases and 3799 controls. The overall results suggested low frequencies of the K17I variant in Caucasian patients (10/2326, 0.43 %) and controls (6/3799, 0.16 %). There is no difference in the variant frequencies between patients with FALS or SALS (p = 0.069). Analysis of pooled odds ratios (ORs) and 95 % confidence intervals (CIs) revealed that the ANG K17I variant increases the risk for ALS (AT vs. AA: OR 2.65, 95 % CI 1.05-6.66, p = 0.038) and familial ALS (FALS) (AT vs. AA: OR 11.81, 95 % CI 2.11-66.15, p = 0.005) but not for sporadic ALS (SALS) (AT vs. AA: OR 1.63, 95 % CI 0.55-4.82, p = 0.378). The ANG K17I variant is rare in Caucasian patients and controls and increases the risk for ALS and FALS but not for SALS in Caucasian populations. Further well-designed studies with larger samples are needed to validate these results.
... Finally, it is noteworthy that in addition to the mutations noted above that cause ALS/FTLD-TDP, multiple pathogenic mutations in four other genes (including those encoding ataxin-2, optineurin, NIPA1 and angiogenin) for ALS and/or FTLD-TDP have been discovered that also are linked to TDP-43 pathology thereby suggesting that ALS and FTLD share similar disease mechanisms all of which involve TDP-43 pathology [86,115,119,145]. Clinicopathological and genetic associations in FTLD/ALS. ...
Frontotemporal lobar degeneration (FTLD) comprises two main classes of neurodegenerative diseases characterized by neuronal/glial proteinaceous inclusions (i.e., proteinopathies) including tauopathies (i.e., FTLD-Tau) and TDP-43 proteinopathies (i.e., FTLD-TDP) while other very rare forms of FTLD are known such as FTLD with FUS pathology (FTLD-FUS). This review focuses mainly on FTLD-Tau and FLTD-TDP, which may present as several clinical syndromes: a behavioral/dysexecutive syndrome (behavioral variant frontotemporal dementia); language disorders (primary progressive aphasia variants); and motor disorders (amyotrophic lateral sclerosis, corticobasal syndrome, progressive supranuclear palsy syndrome). There is considerable heterogeneity in clinical presentations of underlying neuropathology and current clinical criteria do not reliably predict underlying proteinopathies ante-mortem. In contrast, molecular etiologies of hereditary FTLD are consistently associated with specific proteinopathies. These include MAPT mutations with FTLD-Tau and GRN, C9orf72, VCP and TARDBP with FTLD-TDP. The last decade has seen a rapid expansion in our knowledge of the molecular pathologies associated with this clinically and neuropathologically heterogeneous group of FTLD diseases. Moreover, in view of current limitations to reliably diagnose specific FTLD neuropathologies prior to autopsy, we summarize the current state of the science in FTLD biomarker research including neuroimaging, biofluid and genetic analyses. We propose that combining several of these biomarker modalities will improve diagnostic specificity in FTLD through a personalized medicine approach. The goals of these efforts are to enhance power for clinical trials focused on slowing or preventing progression of spread of tau, TDP-43 and other FTLD-associated pathologies and work toward the goal of defining clinical endophenotypes of FTD.
... 122 However, the link between ALS and ANG remains controversial, with reports suggesting it is not associated with unique neuropathology. 124 ANG mutations may cause disease through lossof-function of endogenous angiogenin activity. ANG variants associated with ALS generally lack RNase activity. ...
Genetic insights into the pathophysiology of amyotrophic lateral sclerosis (ALS) are untangling the clinical heterogeneity that may contribute to poor clinical trial outcomes and thus to a lack of effective treatments. Mutations in a large number of genes, including SOD1, C9ORF72, TARDBP, FUS, VAPB, VCP, UBQLN2, ALS2, SETX, OPTN, ANG, and SPG11, are thought to cause ALS, whereas others, including ATAXN2, GRN, HFE, NEFH, UNC13A, and VEGF, appear to be disease-modifying genes. Epigenetic influences may also play important roles. An improved understanding of ALS genetics should lead to better trial designs, insights into common molecular pathways, and better characterization of preclinical models. New genetic sequencing techniques, which use high-throughput methods to assess variants across the genome or exome, may facilitate rational patient stratification for clinical trials and permit more individualized prognostic information and treatment decisions in clinical care. © 2014 Wiley Periodicals, Inc.
... Recent work demonstrates ALS-associated ANG mutations impair the formation of stress granules in neurons 130 , which is interesting in light of the recruitment of TDP-43 and FUS to stress granules. Clinical and neuropathologic features of ANG associated ALS are typical of ALS in general, without discriminating features 131 . ...
Our understanding of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is expanding rapidly as its genetic causes are uncovered. The pace of new gene discovery over the last 5 years has accelerated, providing new insights into the pathogenesis of disease and highlighting biological pathways as targets for therapeutic development. This article reviews our current understanding of the heritability of ALS and provides an overview of each of the major ALS genes, highlighting their phenotypic characteristics and frequencies as a guide for clinicians evaluating patients with ALS.
Angiogenin, an RNase-A-family protein, promotes angiogenesis and has been implicated in cancer, neurodegenerative diseases and epigenetic inheritance1–10. After activation during cellular stress, angiogenin cleaves tRNAs at the anticodon loop, resulting in translation repression11–15. However, the catalytic activity of isolated angiogenin is very low, and the mechanisms of the enzyme activation and tRNA specificity have remained a puzzle3,16–23. Here we identify these mechanisms using biochemical assays and cryogenic electron microscopy (cryo-EM). Our study reveals that the cytosolic ribosome is the activator of angiogenin. A cryo-EM structure features angiogenin bound in the A site of the 80S ribosome. The C-terminal tail of angiogenin is rearranged by interactions with the ribosome to activate the RNase catalytic centre, making the enzyme several orders of magnitude more efficient in tRNA cleavage. Additional 80S–angiogenin structures capture how tRNA substrate is directed by the ribosome into angiogenin’s active site, demonstrating that the ribosome acts as the specificity factor. Our findings therefore suggest that angiogenin is activated by ribosomes with a vacant A site, the abundance of which increases during cellular stress24–27. These results may facilitate the development of therapeutics to treat cancer and neurodegenerative diseases.
