ALS Genetics: Gains, Losses, and Implications for Future Therapies

Kım, Garam; Gautier, Olivia; Tassoni-Tsuchida, Eduardo; Rosa, X.; Gitler, Aaron D.

doi:10.1016/j.neuron.2020.08.022

Cited by 275 publications

(239 citation statements)

References 282 publications

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“…Sporadic forms of the disease are the most abundant (up to 90% of cases), but they are clinically and histopathologically indistinguishable from the different familial forms described so far, which involve mutations in more than 25 ALS‐related genes, among which the most relevant, for different reasons, are (i) SOD1 encoding the key antioxidant enzyme superoxide dismutase‐1; (ii) TARDBP and FUS encoding the proteins TAR‐DNA binding protein‐43 (TDP‐43) or fused in sarcoma (FUS), respectively, involved in pre‐mRNA splicing, transport, and stability; and (iii) C9orf72 encoding a protein involved in intracellular trafficking in neurons and other cell functions not completely understood yet. Changes in SOD‐1, TARDBP , FUS , and C9orf72 are present in most of the cases (approximately 70%) of familial ALS (Kim, Gautier, Tassoni‐Tsuchida, Ma, & Gitler, 2020).…”

Section: Figurementioning

confidence: 99%

Recent advances in the pathogenesis and therapeutics of amyotrophic lateral sclerosis

Fernández‐Ruiz

Lago

Rodríguez‐Cueto

et al. 2021

British J Pharmacology

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Recent advances in the pathogenesis and therapeutics of amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS) is a progressive and highly disabling neurodegenerative disorder, with an incidence of 1-5 cases/100,000 subjects and characterized by muscle denervation, weakness, atrophy, and paralysis, frequently leading to patient death (by respiratory failure) in 3-5 years after diagnosis. The disease starts with a progressive loss of upper and lower motor neurons triggered by a complex aetiology (genes and environmental factors). Sporadic forms of the disease are the most abundant (up to 90% of cases), but they are clinically and histopathologically indistinguishable from the different familial forms described so far, which involve mutations in more than 25 ALS-related genes, among which the most relevant, for different reasons, are (i) SOD1 encoding the key antioxidant enzyme superoxide dismutase-1; (ii) TARDBP and FUS encoding the proteins TAR-DNA binding protein-43 (TDP-43) or fused in sarcoma (FUS), respectively, involved in pre-mRNA splicing, transport, and stability; and (iii) C9orf72 encoding a protein involved in intracellular trafficking in neurons and other cell functions not completely understood yet. Changes in SOD-1, TARDBP, FUS, and C9orf72 are present in most of the cases (approximately 70%) of familial ALS (Kim, Gautier, Tassoni-Tsuchida, Ma, & Gitler, 2020). SOD1 was the first ALS-related gene to be identified in 1993 (Rosen et al., 1993), and its discovery represented an important drive in the research in ALS, in part derived from the rapid development of transgenic animal models (most of them in mice) overexpressing the different human SOD1 mutations (the most abundant being G93A;

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Section: Figurementioning

confidence: 99%

Recent advances in the pathogenesis and therapeutics of amyotrophic lateral sclerosis

Fernández‐Ruiz

Lago

Rodríguez‐Cueto

et al. 2021

British J Pharmacology

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“…Harmful protein oligomerization has been observed to occur in stress granules by TDP-43 [ 57 ] and FUS [ 58 ]. These oligomers, which evolve into amyloid-like conformations, have been reported to harm cells by removing vital activities, by being toxic, or both [ 59 , 60 ]. h-ANG cleaves certain tRNAs to produce fragments that favor a healthy stress response, and based on the results reported here, we conclude that mutations at disease-linked residue positions do not substantially affect protein structure or rigidity.…”

Section: Discussionmentioning

confidence: 99%

NMR Characterization of Angiogenin Variants and tRNAAla Products Impacting Aberrant Protein Oligomerization

Fagagnini

Garavís

Gómez‐Pinto

et al. 2021

IJMS

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Protein oligomerization is key to countless physiological processes, but also to abnormal amyloid conformations implicated in over 25 mortal human diseases. Human Angiogenin (h-ANG), a ribonuclease A family member, produces RNA fragments that regulate ribosome formation, the creation of new blood vessels and stress granule function. Too little h-ANG activity leads to abnormal protein oligomerization, resulting in Amyotrophic Lateral Sclerosis (ALS) or Parkinson’s disease. While a score of disease linked h-ANG mutants has been studied by X-ray diffraction, some elude crystallization. There is also a debate regarding the structure that RNA fragments adopt after cleavage by h-ANG. Here, to better understand the beginning of the process that leads to aberrant protein oligomerization, the solution secondary structure and residue-level dynamics of WT h-ANG and two mutants i.e., H13A and R121C, are characterized by multidimensional heteronuclear NMR spectroscopy under near-physiological conditions. All three variants are found to adopt well folded and highly rigid structures in the solution, although the elements of secondary structure are somewhat shorter than those observed in crystallography studies. R121C alters the environment of nearby residues only. By contrast, the mutation H13A affects local residues as well as nearby active site residues K40 and H114. The conformation characterization by CD and 1D 1H NMR spectroscopies of tRNAAla before and after h-ANG cleavage reveals a retention of the duplex structure and little or no G-quadruplex formation.

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“…Several mutations in seemingly unrelated genes, e.g., superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9orf72), or TAR DNA-binding protein 43 (TARDBP), have been described and it remains possible that ALS is not a single disease entity but a conglomerate of different diseases with a similar clinical endpoint. In most patients, however, no recurrent mutations can be found and for these “sporadic” ALS cases, non-genetic factors might play a role [ 141 , 142 , 143 ].…”

Section: Herv-k In Amyotrophic Lateral Sclerosismentioning

confidence: 99%

Endogenous Retroviruses in Nervous System Disorders

et al. 2021

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Human endogenous retroviruses (HERV) have been implicated in the pathogenesis of several nervous system disorders including multiple sclerosis and amyotrophic lateral sclerosis. The toxicity of HERV-derived RNAs and proteins for neuronal cells has been demonstrated. The involvement of HERV in the pathogenesis of currently incurable diseases might offer new treatment strategies based on the inhibition of HERV activities by small molecules or therapeutic antibodies.

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ALS Genetics: Gains, Losses, and Implications for Future Therapies

Cited by 275 publications

References 282 publications

Recent advances in the pathogenesis and therapeutics of amyotrophic lateral sclerosis

Recent advances in the pathogenesis and therapeutics of amyotrophic lateral sclerosis

NMR Characterization of Angiogenin Variants and tRNAAla Products Impacting Aberrant Protein Oligomerization

Endogenous Retroviruses in Nervous System Disorders

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