Lysosomal dysfunction in Parkinson disease: ATP13A2 gets into the groove.
Identifieur interne : 000831 ( PubMed/Corpus ); précédent : 000830; suivant : 000832Lysosomal dysfunction in Parkinson disease: ATP13A2 gets into the groove.
Auteurs : Benjamin Dehay ; Marta Martinez-Vicente ; Alfredo Ramirez ; Celine Perier ; Christine Klein ; Miquel Vila ; Erwan BezardSource :
- Autophagy [ 1554-8635 ] ; 2012.
English descriptors
- KwdEn :
- Autophagy, Dopaminergic Neurons (metabolism), Dopaminergic Neurons (pathology), Humans, Lewy Bodies (metabolism), Lysosomes (metabolism), Lysosomes (pathology), Parkinson Disease (genetics), Parkinson Disease (physiopathology), Proton-Translocating ATPases (deficiency), Proton-Translocating ATPases (genetics).
- MESH :
- chemical , deficiency : Proton-Translocating ATPases.
- genetics : Parkinson Disease, Proton-Translocating ATPases.
- metabolism : Dopaminergic Neurons, Lewy Bodies, Lysosomes.
- pathology : Dopaminergic Neurons, Lysosomes.
- physiopathology : Parkinson Disease.
- Autophagy, Humans.
Abstract
Mutations in ATP13A2 (PARK9) cause an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia called Kufor-Rakeb Syndrome (KRS). The ATP13A2 gene encodes a transmembrane lysosomal P5-type ATPase (ATP13A2) whose physiological function in mammalian cells, and hence its potential role in Parkinson disease (PD), remains elusive. In this context, we have recently shown that KRS-linked mutations in ATP13A2 leads to several lysosomal alterations in ATP13A2 KRS patient-derived fibroblasts, including impaired lysosomal acidification, decreased proteolytic processing of lysosomal enzymes, reduced degradation of lysosomal substrates and diminished lysosomal-mediated clearance of autophagosomes (AP). Similar alterations are observed in stable ATP13A2-knockdown dopaminergic cell lines, which are associated with cell death. Restoration of ATP13A2 levels in ATP13A2-mutant/depleted cells is able to restore lysosomal function and attenuate cell death. Relevant to PD, we have determined that ATP13A2 levels are decreased in dopaminergic nigral neurons from sporadic PD patients. Interestingly in these patients, the main signal of ATP13A2 is detected in the Lewy bodies. Our results unravel an instrumental role of ATP13A2 in lysosomal function and in cell viability. Altogether, our results validate ATP13A2 as a likely therapeutic target against PD degeneration.
DOI: 10.4161/auto.21011
PubMed: 22885599
Links to Exploration step
pubmed:22885599Le document en format XML
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The ATP13A2 gene encodes a transmembrane lysosomal P5-type ATPase (ATP13A2) whose physiological function in mammalian cells, and hence its potential role in Parkinson disease (PD), remains elusive. In this context, we have recently shown that KRS-linked mutations in ATP13A2 leads to several lysosomal alterations in ATP13A2 KRS patient-derived fibroblasts, including impaired lysosomal acidification, decreased proteolytic processing of lysosomal enzymes, reduced degradation of lysosomal substrates and diminished lysosomal-mediated clearance of autophagosomes (AP). Similar alterations are observed in stable ATP13A2-knockdown dopaminergic cell lines, which are associated with cell death. Restoration of ATP13A2 levels in ATP13A2-mutant/depleted cells is able to restore lysosomal function and attenuate cell death. Relevant to PD, we have determined that ATP13A2 levels are decreased in dopaminergic nigral neurons from sporadic PD patients. Interestingly in these patients, the main signal of ATP13A2 is detected in the Lewy bodies. Our results unravel an instrumental role of ATP13A2 in lysosomal function and in cell viability. Altogether, our results validate ATP13A2 as a likely therapeutic target against PD degeneration.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">22885599</PMID><DateCreated><Year>2012</Year><Month>09</Month><Day>07</Day></DateCreated><DateCompleted><Year>2013</Year><Month>01</Month><Day>16</Day></DateCompleted><DateRevised><Year>2013</Year><Month>09</Month><Day>02</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1554-8635</ISSN><JournalIssue CitedMedium="Internet"><Volume>8</Volume><Issue>9</Issue><PubDate><Year>2012</Year><Month>Sep</Month></PubDate></JournalIssue><Title>Autophagy</Title><ISOAbbreviation>Autophagy</ISOAbbreviation></Journal><ArticleTitle>Lysosomal dysfunction in Parkinson disease: ATP13A2 gets into the groove.</ArticleTitle><Pagination><MedlinePgn>1389-91</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.4161/auto.21011</ELocationID><Abstract><AbstractText>Mutations in ATP13A2 (PARK9) cause an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia called Kufor-Rakeb Syndrome (KRS). The ATP13A2 gene encodes a transmembrane lysosomal P5-type ATPase (ATP13A2) whose physiological function in mammalian cells, and hence its potential role in Parkinson disease (PD), remains elusive. In this context, we have recently shown that KRS-linked mutations in ATP13A2 leads to several lysosomal alterations in ATP13A2 KRS patient-derived fibroblasts, including impaired lysosomal acidification, decreased proteolytic processing of lysosomal enzymes, reduced degradation of lysosomal substrates and diminished lysosomal-mediated clearance of autophagosomes (AP). Similar alterations are observed in stable ATP13A2-knockdown dopaminergic cell lines, which are associated with cell death. Restoration of ATP13A2 levels in ATP13A2-mutant/depleted cells is able to restore lysosomal function and attenuate cell death. Relevant to PD, we have determined that ATP13A2 levels are decreased in dopaminergic nigral neurons from sporadic PD patients. Interestingly in these patients, the main signal of ATP13A2 is detected in the Lewy bodies. Our results unravel an instrumental role of ATP13A2 in lysosomal function and in cell viability. Altogether, our results validate ATP13A2 as a likely therapeutic target against PD degeneration.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Dehay</LastName><ForeName>Benjamin</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Institut des Maladies Neurodégénératives, Université de Bordeaux, CNRS UMR 5293, Bordeaux, France. benjamin.dehay@u-bordeaux2.fr</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Martinez-Vicente</LastName><ForeName>Marta</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Ramirez</LastName><ForeName>Alfredo</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Perier</LastName><ForeName>Celine</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Klein</LastName><ForeName>Christine</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Vila</LastName><ForeName>Miquel</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Bezard</LastName><ForeName>Erwan</ForeName><Initials>E</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2012</Year><Month>08</Month><Day>13</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Autophagy</MedlineTA><NlmUniqueID>101265188</NlmUniqueID><ISSNLinking>1554-8627</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>EC 3.6.3.14</RegistryNumber><NameOfSubstance UI="C514983">ATP13A2 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.6.3.14</RegistryNumber><NameOfSubstance UI="D006180">Proton-Translocating ATPases</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D001343" MajorTopicYN="N">Autophagy</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D059290" MajorTopicYN="N">Dopaminergic Neurons</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016631" MajorTopicYN="N">Lewy Bodies</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008247" MajorTopicYN="N">Lysosomes</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000473" MajorTopicYN="Y">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010300" MajorTopicYN="N">Parkinson Disease</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000503" MajorTopicYN="Y">physiopathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006180" MajorTopicYN="N">Proton-Translocating ATPases</DescriptorName><QualifierName UI="Q000172" MajorTopicYN="N">deficiency</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading></MeshHeadingList><OtherID Source="NLM">PMC3442887</OtherID></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2012</Year><Month>8</Month><Day>14</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2012</Year><Month>8</Month><Day>14</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2013</Year><Month>1</Month><Day>17</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">22885599</ArticleId><ArticleId IdType="pii">21011</ArticleId><ArticleId IdType="doi">10.4161/auto.21011</ArticleId><ArticleId IdType="pmc">PMC3442887</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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