SETX (senataxin), the helicase mutated in AOA2 and ALS4, functions in autophagy regulation.
Identifieur interne : 000051 ( Main/Exploration ); précédent : 000050; suivant : 000052SETX (senataxin), the helicase mutated in AOA2 and ALS4, functions in autophagy regulation.
Auteurs : Patricia Richard [États-Unis] ; Shuang Feng [États-Unis] ; Yueh-Lin Tsai [États-Unis] ; Wencheng Li [États-Unis] ; Paola Rinchetti [États-Unis, Italie] ; Ubayed Muhith [États-Unis] ; Juan Irizarry-Cole [États-Unis] ; Katharine Stolz [États-Unis] ; Lionel A. Sanz [États-Unis] ; Stella Hartono [États-Unis] ; Mainul Hoque [États-Unis] ; Saba Tadesse [États-Unis] ; Hervé Seitz [France] ; Francesco Lotti [États-Unis] ; Michio Hirano [États-Unis] ; Frédéric Chédin [États-Unis] ; Bin Tian [États-Unis] ; James L. Manley [États-Unis]Source :
- Autophagy [ 1554-8635 ] ; 2020.
Abstract
SETX (senataxin) is an RNA/DNA helicase that has been implicated in transcriptional regulation and the DNA damage response through resolution of R-loop structures. Mutations in SETX result in either of two distinct neurodegenerative disorders. SETX dominant mutations result in a juvenile form of amyotrophic lateral sclerosis (ALS) called ALS4, whereas recessive mutations are responsible for ataxia called ataxia with oculomotor apraxia type 2 (AOA2). How mutations in the same protein can lead to different phenotypes is still unclear. To elucidate AOA2 disease mechanisms, we first examined gene expression changes following SETX depletion. We observed the effects on both transcription and RNA processing, but surprisingly observed decreased R-loop accumulation in SETX-depleted cells. Importantly, we discovered a strong connection between SETX and the macroautophagy/autophagy pathway, reflecting a direct effect on transcription of autophagy genes. We show that SETX depletion inhibits the progression of autophagy, leading to an accumulation of ubiquitinated proteins, decreased ability to clear protein aggregates, as well as mitochondrial defects. Analysis of AOA2 patient fibroblasts also revealed a perturbation of the autophagy pathway. Our work has thus identified a novel function for SETX in the regulation of autophagy, whose modulation may have a therapeutic impact for AOA2.
ABBREVIATIONS
3'READS: 3' region extraction and deep sequencing; ACTB: actin beta; ALS4: amyotrophic lateral sclerosis type 4; AOA2: ataxia with oculomotor apraxia type 2; APA: alternative polyadenylation; AS: alternative splicing; ATG7: autophagy-related 7; ATP6V0D2: ATPase H+ transporting V0 subunit D2; BAF: bafilomycin A
DOI: 10.1080/15548627.2020.1796292
PubMed: 32686621
Affiliations:
- France, Italie, États-Unis
- Californie, Languedoc-Roussillon, Lombardie, New Jersey, Occitanie (région administrative), Pennsylvanie, État de New York
- Milan, Montpellier
Links toward previous steps (curation, corpus...)
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de New York</region></placeName></affiliation></author><author><name sortKey="Li, Wencheng" sort="Li, Wencheng" uniqKey="Li W" first="Wencheng" last="Li">Wencheng Li</name><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School , Newark, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School , Newark, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Rinchetti, Paola" sort="Rinchetti, Paola" uniqKey="Rinchetti P" first="Paola" last="Rinchetti">Paola Rinchetti</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology and Cell Biology, Columbia University Irving Medical Center , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology and Cell Biology, Columbia University Irving Medical Center , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), University of Milan , Milan, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), University of Milan , Milan</wicri:regionArea><placeName><settlement type="city">Milan</settlement><region nuts="2">Lombardie</region></placeName></affiliation></author><author><name sortKey="Muhith, Ubayed" sort="Muhith, Ubayed" uniqKey="Muhith U" first="Ubayed" last="Muhith">Ubayed Muhith</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Sciences, Columbia University , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Irizarry Cole, Juan" sort="Irizarry Cole, Juan" uniqKey="Irizarry Cole J" first="Juan" last="Irizarry-Cole">Juan Irizarry-Cole</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Sciences, Columbia University , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Stolz, Katharine" sort="Stolz, Katharine" uniqKey="Stolz K" first="Katharine" last="Stolz">Katharine Stolz</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Sciences, Columbia University , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Sanz, Lionel A" sort="Sanz, Lionel A" uniqKey="Sanz L" first="Lionel A" last="Sanz">Lionel A. 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type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Hoque, Mainul" sort="Hoque, Mainul" uniqKey="Hoque M" first="Mainul" last="Hoque">Mainul Hoque</name><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School , Newark, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School , Newark, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Tadesse, Saba" sort="Tadesse, Saba" uniqKey="Tadesse S" first="Saba" last="Tadesse">Saba Tadesse</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neurology, Columbia University Irving Medical Center , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Columbia University Irving Medical Center , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Seitz, Herve" sort="Seitz, Herve" uniqKey="Seitz H" first="Hervé" last="Seitz">Hervé Seitz</name><affiliation wicri:level="3"><nlm:affiliation>Institut de Génétique Humaine, UMR 9002 CNRS and Université de Montpellier , Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Humaine, UMR 9002 CNRS and Université de Montpellier , Montpellier</wicri:regionArea><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName></affiliation></author><author><name sortKey="Lotti, Francesco" sort="Lotti, Francesco" uniqKey="Lotti F" first="Francesco" last="Lotti">Francesco Lotti</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology and Cell Biology, Columbia University Irving Medical Center , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology and Cell Biology, Columbia University Irving Medical Center , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Hirano, Michio" sort="Hirano, Michio" uniqKey="Hirano M" first="Michio" last="Hirano">Michio Hirano</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neurology, Columbia University Irving Medical Center , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Columbia University Irving Medical Center , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Chedin, Frederic" sort="Chedin, Frederic" uniqKey="Chedin F" first="Frédéric" last="Chédin">Frédéric Chédin</name><affiliation wicri:level="2"><nlm:affiliation>Department of Molecular and Cellular Biology and Genome Center, University of California , Davis, CA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular and Cellular Biology and Genome Center, University of California , Davis, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Tian, Bin" sort="Tian, Bin" uniqKey="Tian B" first="Bin" last="Tian">Bin Tian</name><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School , Newark, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School , Newark, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>Gene Expression and Regulation Program, and Center for Systems and Computational Biology, The Wistar Institute , Philadelphia, PA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Gene Expression and Regulation Program, and Center for Systems and Computational Biology, The Wistar Institute , Philadelphia, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Manley, James L" sort="Manley, James L" uniqKey="Manley J" first="James L" last="Manley">James L. Manley</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Sciences, Columbia University , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32686621</idno><idno type="pmid">32686621</idno><idno type="doi">10.1080/15548627.2020.1796292</idno><idno type="wicri:Area/Main/Corpus">000041</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000041</idno><idno type="wicri:Area/Main/Curation">000041</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000041</idno><idno type="wicri:Area/Main/Exploration">000041</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">SETX (senataxin), the helicase mutated in AOA2 and ALS4, functions in autophagy regulation.</title><author><name sortKey="Richard, Patricia" sort="Richard, Patricia" uniqKey="Richard P" first="Patricia" last="Richard">Patricia Richard</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Sciences, Columbia University , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>Stellate Therapeutics, JLABS @ NYC , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Stellate Therapeutics, JLABS @ NYC , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Feng, Shuang" sort="Feng, Shuang" uniqKey="Feng S" first="Shuang" last="Feng">Shuang Feng</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Sciences, Columbia University , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Tsai, Yueh Lin" sort="Tsai, Yueh Lin" uniqKey="Tsai Y" first="Yueh-Lin" last="Tsai">Yueh-Lin Tsai</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Sciences, Columbia University , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Li, Wencheng" sort="Li, Wencheng" uniqKey="Li W" first="Wencheng" last="Li">Wencheng Li</name><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School , Newark, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School , Newark, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Rinchetti, Paola" sort="Rinchetti, Paola" uniqKey="Rinchetti P" first="Paola" last="Rinchetti">Paola Rinchetti</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology and Cell Biology, Columbia University Irving Medical Center , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology and Cell Biology, Columbia University Irving Medical Center , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), University of Milan , Milan, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), University of Milan , Milan</wicri:regionArea><placeName><settlement type="city">Milan</settlement><region nuts="2">Lombardie</region></placeName></affiliation></author><author><name sortKey="Muhith, Ubayed" sort="Muhith, Ubayed" uniqKey="Muhith U" first="Ubayed" last="Muhith">Ubayed Muhith</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Sciences, Columbia University , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Irizarry Cole, Juan" sort="Irizarry Cole, Juan" uniqKey="Irizarry Cole J" first="Juan" last="Irizarry-Cole">Juan Irizarry-Cole</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Sciences, Columbia University , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Stolz, Katharine" sort="Stolz, Katharine" uniqKey="Stolz K" first="Katharine" last="Stolz">Katharine Stolz</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Sciences, Columbia University , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Sanz, Lionel A" sort="Sanz, Lionel A" uniqKey="Sanz L" first="Lionel A" last="Sanz">Lionel A. Sanz</name><affiliation wicri:level="2"><nlm:affiliation>Department of Molecular and Cellular Biology and Genome Center, University of California , Davis, CA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular and Cellular Biology and Genome Center, University of California , Davis, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Hartono, Stella" sort="Hartono, Stella" uniqKey="Hartono S" first="Stella" last="Hartono">Stella Hartono</name><affiliation wicri:level="2"><nlm:affiliation>Department of Molecular and Cellular Biology and Genome Center, University of California , Davis, CA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular and Cellular Biology and Genome Center, University of California , Davis, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Hoque, Mainul" sort="Hoque, Mainul" uniqKey="Hoque M" first="Mainul" last="Hoque">Mainul Hoque</name><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School , Newark, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School , Newark, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Tadesse, Saba" sort="Tadesse, Saba" uniqKey="Tadesse S" first="Saba" last="Tadesse">Saba Tadesse</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neurology, Columbia University Irving Medical Center , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Columbia University Irving Medical Center , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Seitz, Herve" sort="Seitz, Herve" uniqKey="Seitz H" first="Hervé" last="Seitz">Hervé Seitz</name><affiliation wicri:level="3"><nlm:affiliation>Institut de Génétique Humaine, UMR 9002 CNRS and Université de Montpellier , Montpellier, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Génétique Humaine, UMR 9002 CNRS and Université de Montpellier , Montpellier</wicri:regionArea><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName></affiliation></author><author><name sortKey="Lotti, Francesco" sort="Lotti, Francesco" uniqKey="Lotti F" first="Francesco" last="Lotti">Francesco Lotti</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology and Cell Biology, Columbia University Irving Medical Center , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology and Cell Biology, Columbia University Irving Medical Center , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Hirano, Michio" sort="Hirano, Michio" uniqKey="Hirano M" first="Michio" last="Hirano">Michio Hirano</name><affiliation wicri:level="2"><nlm:affiliation>Department of Neurology, Columbia University Irving Medical Center , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Columbia University Irving Medical Center , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Chedin, Frederic" sort="Chedin, Frederic" uniqKey="Chedin F" first="Frédéric" last="Chédin">Frédéric Chédin</name><affiliation wicri:level="2"><nlm:affiliation>Department of Molecular and Cellular Biology and Genome Center, University of California , Davis, CA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular and Cellular Biology and Genome Center, University of California , Davis, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Tian, Bin" sort="Tian, Bin" uniqKey="Tian B" first="Bin" last="Tian">Bin Tian</name><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School , Newark, NJ, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School , Newark, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>Gene Expression and Regulation Program, and Center for Systems and Computational Biology, The Wistar Institute , Philadelphia, PA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Gene Expression and Regulation Program, and Center for Systems and Computational Biology, The Wistar Institute , Philadelphia, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Manley, James L" sort="Manley, James L" uniqKey="Manley J" first="James L" last="Manley">James L. Manley</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Sciences, Columbia University , New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author></analytic><series><title level="j">Autophagy</title><idno type="eISSN">1554-8635</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">SETX (senataxin) is an RNA/DNA helicase that has been implicated in transcriptional regulation and the DNA damage response through resolution of R-loop structures. Mutations in <i>SETX</i> result in either of two distinct neurodegenerative disorders. <i>SETX</i> dominant mutations result in a juvenile form of amyotrophic lateral sclerosis (ALS) called ALS4, whereas recessive mutations are responsible for ataxia called ataxia with oculomotor apraxia type 2 (AOA2). How mutations in the same protein can lead to different phenotypes is still unclear. To elucidate AOA2 disease mechanisms, we first examined gene expression changes following SETX depletion. We observed the effects on both transcription and RNA processing, but surprisingly observed decreased R-loop accumulation in SETX-depleted cells. Importantly, we discovered a strong connection between SETX and the macroautophagy/autophagy pathway, reflecting a direct effect on transcription of autophagy genes. We show that SETX depletion inhibits the progression of autophagy, leading to an accumulation of ubiquitinated proteins, decreased ability to clear protein aggregates, as well as mitochondrial defects. Analysis of AOA2 patient fibroblasts also revealed a perturbation of the autophagy pathway. Our work has thus identified a novel function for SETX in the regulation of autophagy, whose modulation may have a therapeutic impact for AOA2.</div><div type="abstract" xml:lang="en"><p><b>ABBREVIATIONS</b></p><p>3'READS: 3' region extraction and deep sequencing; ACTB: actin beta; ALS4: amyotrophic lateral sclerosis type 4; AOA2: ataxia with oculomotor apraxia type 2; APA: alternative polyadenylation; AS: alternative splicing; ATG7: autophagy-related 7; ATP6V0D2: ATPase H+ transporting V0 subunit D2; BAF: bafilomycin A</p></div></front></TEI><pubmed><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">32686621</PMID><DateRevised><Year>2020</Year><Month>11</Month><Day>04</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1554-8635</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2020</Year><Month>Aug</Month><Day>07</Day></PubDate></JournalIssue><Title>Autophagy</Title><ISOAbbreviation>Autophagy</ISOAbbreviation></Journal><ArticleTitle>SETX (senataxin), the helicase mutated in AOA2 and ALS4, functions in autophagy regulation.</ArticleTitle><Pagination><MedlinePgn>1-18</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1080/15548627.2020.1796292</ELocationID><Abstract><AbstractText>SETX (senataxin) is an RNA/DNA helicase that has been implicated in transcriptional regulation and the DNA damage response through resolution of R-loop structures. Mutations in <i>SETX</i> result in either of two distinct neurodegenerative disorders. <i>SETX</i> dominant mutations result in a juvenile form of amyotrophic lateral sclerosis (ALS) called ALS4, whereas recessive mutations are responsible for ataxia called ataxia with oculomotor apraxia type 2 (AOA2). How mutations in the same protein can lead to different phenotypes is still unclear. To elucidate AOA2 disease mechanisms, we first examined gene expression changes following SETX depletion. We observed the effects on both transcription and RNA processing, but surprisingly observed decreased R-loop accumulation in SETX-depleted cells. Importantly, we discovered a strong connection between SETX and the macroautophagy/autophagy pathway, reflecting a direct effect on transcription of autophagy genes. We show that SETX depletion inhibits the progression of autophagy, leading to an accumulation of ubiquitinated proteins, decreased ability to clear protein aggregates, as well as mitochondrial defects. Analysis of AOA2 patient fibroblasts also revealed a perturbation of the autophagy pathway. Our work has thus identified a novel function for SETX in the regulation of autophagy, whose modulation may have a therapeutic impact for AOA2.</AbstractText><AbstractText Label="ABBREVIATIONS" NlmCategory="BACKGROUND">3'READS: 3' region extraction and deep sequencing; ACTB: actin beta; ALS4: amyotrophic lateral sclerosis type 4; AOA2: ataxia with oculomotor apraxia type 2; APA: alternative polyadenylation; AS: alternative splicing; ATG7: autophagy-related 7; ATP6V0D2: ATPase H+ transporting V0 subunit D2; BAF: bafilomycin A<sub>1</sub>; BECN1: beclin 1; ChIP: chromatin IP; Chloro: chloroquine; CPT: camptothecin; DDR: DNA damage response; DNMT1: DNA methyltransferase 1; DRIP: DNA/RNA IP; DSBs: double strand breaks; EBs: embryoid bodies; FTD: frontotemporal dementia; GABARAP: GABA type A receptor-associated protein; GO: gene ontology; HR: homologous recombination; HTT: huntingtin; IF: immunofluorescence; IP: immunoprecipitation; iPSCs: induced pluripotent stem cells; KD: knockdown; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MN: motor neuron; MTORC1: mechanistic target of rapamycin kinase complex 1; PASS: PolyA Site Supporting; PFA: paraformaldehyde; RNAPII: RNA polymerase II; SCA: spinocerebellar ataxia; SETX: senataxin; SMA: spinal muscular atrophy; SMN1: survival of motor neuron 1, telomeric; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TSS: transcription start site; TTS: transcription termination site; ULK1: unc-51 like autophagy activating kinase 1; WB: western blot; WIPI2: WD repeat domain, phosphoinositide interacting 2; XRN2: 5'-3' exoribonuclease 2.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Richard</LastName><ForeName>Patricia</ForeName><Initials>P</Initials><Identifier Source="ORCID">https://orcid.org/0000-0002-9515-4509</Identifier><AffiliationInfo><Affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Stellate Therapeutics, JLABS @ NYC , New York, NY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Feng</LastName><ForeName>Shuang</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tsai</LastName><ForeName>Yueh-Lin</ForeName><Initials>YL</Initials><AffiliationInfo><Affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Wencheng</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School , Newark, NJ, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rinchetti</LastName><ForeName>Paola</ForeName><Initials>P</Initials><Identifier Source="ORCID">https://orcid.org/0000-0001-8279-3304</Identifier><AffiliationInfo><Affiliation>Department of Pathology and Cell Biology, Columbia University Irving Medical Center , New York, NY, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), University of Milan , Milan, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Muhith</LastName><ForeName>Ubayed</ForeName><Initials>U</Initials><AffiliationInfo><Affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Irizarry-Cole</LastName><ForeName>Juan</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stolz</LastName><ForeName>Katharine</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sanz</LastName><ForeName>Lionel A</ForeName><Initials>LA</Initials><AffiliationInfo><Affiliation>Department of Molecular and Cellular Biology and Genome Center, University of California , Davis, CA, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hartono</LastName><ForeName>Stella</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Molecular and Cellular Biology and Genome Center, University of California , Davis, CA, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hoque</LastName><ForeName>Mainul</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School , Newark, NJ, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tadesse</LastName><ForeName>Saba</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Neurology, Columbia University Irving Medical Center , New York, NY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Seitz</LastName><ForeName>Hervé</ForeName><Initials>H</Initials><Identifier Source="ORCID">https://orcid.org/0000-0001-8172-5393</Identifier><AffiliationInfo><Affiliation>Institut de Génétique Humaine, UMR 9002 CNRS and Université de Montpellier , Montpellier, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lotti</LastName><ForeName>Francesco</ForeName><Initials>F</Initials><Identifier Source="ORCID">https://orcid.org/0000-0002-5104-9088</Identifier><AffiliationInfo><Affiliation>Department of Pathology and Cell Biology, Columbia University Irving Medical Center , New York, NY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hirano</LastName><ForeName>Michio</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Neurology, Columbia University Irving Medical Center , New York, NY, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chédin</LastName><ForeName>Frédéric</ForeName><Initials>F</Initials><Identifier Source="ORCID">https://orcid.org/0000-0002-1306-5335</Identifier><AffiliationInfo><Affiliation>Department of Molecular and Cellular Biology and Genome Center, University of California , Davis, CA, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tian</LastName><ForeName>Bin</ForeName><Initials>B</Initials><Identifier Source="ORCID">https://orcid.org/0000-0001-8903-8256</Identifier><AffiliationInfo><Affiliation>Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School , Newark, NJ, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Gene Expression and Regulation Program, and Center for Systems and Computational Biology, The Wistar Institute , Philadelphia, PA, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Manley</LastName><ForeName>James L</ForeName><Initials>JL</Initials><AffiliationInfo><Affiliation>Department of Biological Sciences, Columbia University , New York, NY, USA.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>P30 CA010815</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 GM120607</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>08</Month><Day>07</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Autophagy</MedlineTA><NlmUniqueID>101265188</NlmUniqueID><ISSNLinking>1554-8627</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">AOA2</Keyword><Keyword MajorTopicYN="N">DRIP</Keyword><Keyword MajorTopicYN="N">LC3</Keyword><Keyword MajorTopicYN="N">R loop</Keyword><Keyword MajorTopicYN="N">R-loop</Keyword><Keyword MajorTopicYN="N">SETX</Keyword><Keyword MajorTopicYN="N">autophagy</Keyword><Keyword MajorTopicYN="N">lysosomal degradation</Keyword><Keyword MajorTopicYN="N">senataxin</Keyword><Keyword MajorTopicYN="N">transcription regulation</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>7</Month><Day>21</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>7</Month><Day>21</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>7</Month><Day>21</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>aheadofprint</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">32686621</ArticleId><ArticleId IdType="doi">10.1080/15548627.2020.1796292</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>France</li><li>Italie</li><li>États-Unis</li></country><region><li>Californie</li><li>Languedoc-Roussillon</li><li>Lombardie</li><li>New Jersey</li><li>Occitanie (région administrative)</li><li>Pennsylvanie</li><li>État de New York</li></region><settlement><li>Milan</li><li>Montpellier</li></settlement></list><tree><country name="États-Unis"><region name="État de New York"><name sortKey="Richard, Patricia" sort="Richard, Patricia" uniqKey="Richard P" first="Patricia" last="Richard">Patricia Richard</name></region><name sortKey="Chedin, Frederic" sort="Chedin, Frederic" uniqKey="Chedin F" first="Frédéric" last="Chédin">Frédéric Chédin</name><name sortKey="Feng, Shuang" sort="Feng, Shuang" uniqKey="Feng S" first="Shuang" last="Feng">Shuang Feng</name><name sortKey="Hartono, Stella" sort="Hartono, Stella" uniqKey="Hartono S" first="Stella" last="Hartono">Stella Hartono</name><name sortKey="Hirano, Michio" sort="Hirano, Michio" uniqKey="Hirano M" first="Michio" last="Hirano">Michio Hirano</name><name sortKey="Hoque, Mainul" sort="Hoque, Mainul" uniqKey="Hoque M" first="Mainul" last="Hoque">Mainul Hoque</name><name sortKey="Irizarry Cole, Juan" sort="Irizarry Cole, Juan" uniqKey="Irizarry Cole J" first="Juan" last="Irizarry-Cole">Juan Irizarry-Cole</name><name sortKey="Li, Wencheng" sort="Li, Wencheng" uniqKey="Li W" first="Wencheng" last="Li">Wencheng Li</name><name sortKey="Lotti, Francesco" sort="Lotti, Francesco" uniqKey="Lotti F" first="Francesco" last="Lotti">Francesco Lotti</name><name sortKey="Manley, James L" sort="Manley, James L" uniqKey="Manley J" first="James L" last="Manley">James L. Manley</name><name sortKey="Muhith, Ubayed" sort="Muhith, Ubayed" uniqKey="Muhith U" first="Ubayed" last="Muhith">Ubayed Muhith</name><name sortKey="Richard, Patricia" sort="Richard, Patricia" uniqKey="Richard P" first="Patricia" last="Richard">Patricia Richard</name><name sortKey="Rinchetti, Paola" sort="Rinchetti, Paola" uniqKey="Rinchetti P" first="Paola" last="Rinchetti">Paola Rinchetti</name><name sortKey="Sanz, Lionel A" sort="Sanz, Lionel A" uniqKey="Sanz L" first="Lionel A" last="Sanz">Lionel A. Sanz</name><name sortKey="Stolz, Katharine" sort="Stolz, Katharine" uniqKey="Stolz K" first="Katharine" last="Stolz">Katharine Stolz</name><name sortKey="Tadesse, Saba" sort="Tadesse, Saba" uniqKey="Tadesse S" first="Saba" last="Tadesse">Saba Tadesse</name><name sortKey="Tian, Bin" sort="Tian, Bin" uniqKey="Tian B" first="Bin" last="Tian">Bin Tian</name><name sortKey="Tian, Bin" sort="Tian, Bin" uniqKey="Tian B" first="Bin" last="Tian">Bin Tian</name><name sortKey="Tsai, Yueh Lin" sort="Tsai, Yueh Lin" uniqKey="Tsai Y" first="Yueh-Lin" last="Tsai">Yueh-Lin Tsai</name></country><country name="Italie"><region name="Lombardie"><name sortKey="Rinchetti, Paola" sort="Rinchetti, Paola" uniqKey="Rinchetti P" first="Paola" last="Rinchetti">Paola Rinchetti</name></region></country><country name="France"><region name="Occitanie (région administrative)"><name sortKey="Seitz, Herve" sort="Seitz, Herve" uniqKey="Seitz H" first="Hervé" last="Seitz">Hervé Seitz</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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