Friedreich ataxia- pathogenesis and implications for therapies.
Identifieur interne : 000238 ( Main/Exploration ); précédent : 000237; suivant : 000239Friedreich ataxia- pathogenesis and implications for therapies.
Auteurs : Martin B. Delatycki [Australie] ; Sanjay I. Bidichandani [États-Unis]Source :
- Neurobiology of disease [ 1095-953X ] ; 2019.
Descripteurs français
- KwdFr :
- MESH :
- génétique : Ataxie de Friedreich.
- physiopathologie : Ataxie de Friedreich.
- thérapie : Ataxie de Friedreich.
- Animaux, Humains.
English descriptors
- KwdEn :
- MESH :
- genetics : Friedreich Ataxia.
- physiopathology : Friedreich Ataxia.
- therapy : Friedreich Ataxia.
- Animals, Humans.
Abstract
Friedreich ataxia is the most common of the hereditary ataxias. It is due to homozygous/compound heterozygous mutations in FXN. This gene encodes frataxin, a protein largely localized to mitochondria. In about 96% of affected individuals there is homozygosity for a GAA repeat expansion in intron 1 of the FXN gene. Studies of people with Friedreich ataxia and of animal and cell models, have provided much insight into the pathogenesis of this disorder. The expanded GAA repeat leads to transcriptional deficiency of the FXN gene. The consequent deficiency of frataxin protein leads to reduced iron-sulfur cluster biogenesis and mitochondrial ATP production, elevated mitochondrial iron, and oxidative stress. More recently, a role for inflammation has emerged as being important in the pathogenesis of Friedreich ataxia. These findings have led to a number of potential therapies that have been subjected to clinical trials or are being developed toward human studies. Therapies that have been proposed include pharmaceuticals that increase frataxin levels, protein and gene replacement therapies, antioxidants, iron chelators and modulators of inflammation. Whilst no therapies have yet been approved for Friedreich ataxia, there is much optimism that the advances in the understanding of the pathogenesis of this disorder since the discovery its genetic basis, will result in approved disease modifying therapies in the near future.
DOI: 10.1016/j.nbd.2019.104606
PubMed: 31494282
Affiliations:
Links toward previous steps (curation, corpus...)
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Electronic address: martin.delatycki@vcgs.org.au.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Bruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Victorian Clinical Genetics Services, Parkville, Victoria, Australia; Department of Paediatrics, University of Melbourne, Parkville, Victoria</wicri:regionArea><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Bidichandani, Sanjay I" sort="Bidichandani, Sanjay I" uniqKey="Bidichandani S" first="Sanjay I" last="Bidichandani">Sanjay I. Bidichandani</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK</wicri:regionArea><placeName><region type="state">Oklahoma</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2019">2019</date><idno type="RBID">pubmed:31494282</idno><idno type="pmid">31494282</idno><idno type="doi">10.1016/j.nbd.2019.104606</idno><idno type="wicri:Area/Main/Corpus">000240</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000240</idno><idno type="wicri:Area/Main/Curation">000240</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000240</idno><idno type="wicri:Area/Main/Exploration">000240</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Friedreich ataxia- pathogenesis and implications for therapies.</title><author><name sortKey="Delatycki, Martin B" sort="Delatycki, Martin B" uniqKey="Delatycki M" first="Martin B" last="Delatycki">Martin B. Delatycki</name><affiliation wicri:level="4"><nlm:affiliation>Bruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Victorian Clinical Genetics Services, Parkville, Victoria, Australia; Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia. Electronic address: martin.delatycki@vcgs.org.au.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Bruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Victorian Clinical Genetics Services, Parkville, Victoria, Australia; Department of Paediatrics, University of Melbourne, Parkville, Victoria</wicri:regionArea><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Bidichandani, Sanjay I" sort="Bidichandani, Sanjay I" uniqKey="Bidichandani S" first="Sanjay I" last="Bidichandani">Sanjay I. Bidichandani</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK</wicri:regionArea><placeName><region type="state">Oklahoma</region></placeName></affiliation></author></analytic><series><title level="j">Neurobiology of disease</title><idno type="eISSN">1095-953X</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term><term>Friedreich Ataxia (genetics)</term><term>Friedreich Ataxia (physiopathology)</term><term>Friedreich Ataxia (therapy)</term><term>Humans (MeSH)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term><term>Ataxie de Friedreich (génétique)</term><term>Ataxie de Friedreich (physiopathologie)</term><term>Ataxie de Friedreich (thérapie)</term><term>Humains (MeSH)</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Friedreich Ataxia</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Ataxie de Friedreich</term></keywords><keywords scheme="MESH" qualifier="physiopathologie" xml:lang="fr"><term>Ataxie de Friedreich</term></keywords><keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Friedreich Ataxia</term></keywords><keywords scheme="MESH" qualifier="therapy" xml:lang="en"><term>Friedreich Ataxia</term></keywords><keywords scheme="MESH" qualifier="thérapie" xml:lang="fr"><term>Ataxie de Friedreich</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Humans</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Humains</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Friedreich ataxia is the most common of the hereditary ataxias. It is due to homozygous/compound heterozygous mutations in FXN. This gene encodes frataxin, a protein largely localized to mitochondria. In about 96% of affected individuals there is homozygosity for a GAA repeat expansion in intron 1 of the FXN gene. Studies of people with Friedreich ataxia and of animal and cell models, have provided much insight into the pathogenesis of this disorder. The expanded GAA repeat leads to transcriptional deficiency of the FXN gene. The consequent deficiency of frataxin protein leads to reduced iron-sulfur cluster biogenesis and mitochondrial ATP production, elevated mitochondrial iron, and oxidative stress. More recently, a role for inflammation has emerged as being important in the pathogenesis of Friedreich ataxia. These findings have led to a number of potential therapies that have been subjected to clinical trials or are being developed toward human studies. Therapies that have been proposed include pharmaceuticals that increase frataxin levels, protein and gene replacement therapies, antioxidants, iron chelators and modulators of inflammation. Whilst no therapies have yet been approved for Friedreich ataxia, there is much optimism that the advances in the understanding of the pathogenesis of this disorder since the discovery its genetic basis, will result in approved disease modifying therapies in the near future.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">31494282</PMID><DateCompleted><Year>2020</Year><Month>08</Month><Day>06</Day></DateCompleted><DateRevised><Year>2020</Year><Month>08</Month><Day>06</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1095-953X</ISSN><JournalIssue CitedMedium="Internet"><Volume>132</Volume><PubDate><Year>2019</Year><Month>12</Month></PubDate></JournalIssue><Title>Neurobiology of disease</Title><ISOAbbreviation>Neurobiol Dis</ISOAbbreviation></Journal><ArticleTitle>Friedreich ataxia- pathogenesis and implications for therapies.</ArticleTitle><Pagination><MedlinePgn>104606</MedlinePgn></Pagination><ELocationID EIdType="pii" ValidYN="Y">S0969-9961(19)30281-5</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.nbd.2019.104606</ELocationID><Abstract><AbstractText>Friedreich ataxia is the most common of the hereditary ataxias. It is due to homozygous/compound heterozygous mutations in FXN. This gene encodes frataxin, a protein largely localized to mitochondria. In about 96% of affected individuals there is homozygosity for a GAA repeat expansion in intron 1 of the FXN gene. Studies of people with Friedreich ataxia and of animal and cell models, have provided much insight into the pathogenesis of this disorder. The expanded GAA repeat leads to transcriptional deficiency of the FXN gene. The consequent deficiency of frataxin protein leads to reduced iron-sulfur cluster biogenesis and mitochondrial ATP production, elevated mitochondrial iron, and oxidative stress. More recently, a role for inflammation has emerged as being important in the pathogenesis of Friedreich ataxia. These findings have led to a number of potential therapies that have been subjected to clinical trials or are being developed toward human studies. Therapies that have been proposed include pharmaceuticals that increase frataxin levels, protein and gene replacement therapies, antioxidants, iron chelators and modulators of inflammation. Whilst no therapies have yet been approved for Friedreich ataxia, there is much optimism that the advances in the understanding of the pathogenesis of this disorder since the discovery its genetic basis, will result in approved disease modifying therapies in the near future.</AbstractText><CopyrightInformation>Copyright © 2019 Elsevier Inc. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Delatycki</LastName><ForeName>Martin B</ForeName><Initials>MB</Initials><AffiliationInfo><Affiliation>Bruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Victorian Clinical Genetics Services, Parkville, Victoria, Australia; Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia. Electronic address: martin.delatycki@vcgs.org.au.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bidichandani</LastName><ForeName>Sanjay I</ForeName><Initials>SI</Initials><AffiliationInfo><Affiliation>Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2019</Year><Month>09</Month><Day>05</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Neurobiol Dis</MedlineTA><NlmUniqueID>9500169</NlmUniqueID><ISSNLinking>0969-9961</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005621" MajorTopicYN="N">Friedreich Ataxia</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000503" MajorTopicYN="Y">physiopathology</QualifierName><QualifierName UI="Q000628" MajorTopicYN="Y">therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2019</Year><Month>06</Month><Day>25</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2019</Year><Month>08</Month><Day>08</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2019</Year><Month>09</Month><Day>04</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2019</Year><Month>9</Month><Day>9</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>8</Month><Day>7</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2019</Year><Month>9</Month><Day>9</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">31494282</ArticleId><ArticleId IdType="pii">S0969-9961(19)30281-5</ArticleId><ArticleId IdType="doi">10.1016/j.nbd.2019.104606</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Australie</li><li>États-Unis</li></country><region><li>Oklahoma</li><li>Victoria (État)</li></region><settlement><li>Melbourne</li></settlement><orgName><li>Université de Melbourne</li></orgName></list><tree><country name="Australie"><region name="Victoria (État)"><name sortKey="Delatycki, Martin B" sort="Delatycki, Martin B" uniqKey="Delatycki M" first="Martin B" last="Delatycki">Martin B. Delatycki</name></region></country><country name="États-Unis"><region name="Oklahoma"><name sortKey="Bidichandani, Sanjay I" sort="Bidichandani, Sanjay I" uniqKey="Bidichandani S" first="Sanjay I" last="Bidichandani">Sanjay I. Bidichandani</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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