Interaction between parkin and mutant glucocerebrosidase variants: a possible link between Parkinson disease and Gaucher disease
Identifieur interne : 000459 ( Main/Exploration ); précédent : 000458; suivant : 000460Interaction between parkin and mutant glucocerebrosidase variants: a possible link between Parkinson disease and Gaucher disease
Auteurs : Idit Ron [Israël] ; Debora Rapaport [Israël] ; Mia Horowitz [Israël]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-10-01.
Abstract
Gaucher disease (GD), a sphingolipidosis characterized by impaired activity of the lysosomal enzyme glucocerebrosidase (GCase), results from mutations in the GCase-encoding gene, GBA. We have shown that mutant GCase variants present variable degrees of endoplasmic reticulum (ER) retention and undergo ER-associated degradation (ERAD) in the proteasome. Furthermore, the degree of ERAD of mutant GCase variants correlates with and is one of the factors that determine GD severity. An association between GD and Parkinson disease (PD) has been demonstrated by the concurrence of PD in GD patients and the identification of GCase mutations in probands with sporadic PD. One of the genes involved in PD is PARK2, encoding the E3 ubiquitin ligase parkin. Parkin functions in the ERAD of misfolded ER proteins, and it is upregulated by unfolded protein response. Loss of parkin function leads to the accumulation of its substrates, which is deleterious to dopaminergic neurons in PD. We, therefore, tested the possibility that the association between GD and PD reflects the fact that parkin acts as an E3 ligase of mutant GCase variants. Our results showed that mutant GCase variants associate with parkin. Normal parkin, but not its RING finger mutants, affects the stability of mutant GCase variants. Parkin also promotes the accumulation of mutant GCase in aggresome-like structures and is involved in K48-mediated polyubiquitination of GCase mutants, indicating its function as its E3 ligase. We suggest that involvement of parkin in the degradation of mutant GCase explains the concurrence of GD and PD.
Url:
DOI: 10.1093/hmg/ddq292
Affiliations:
Links toward previous steps (curation, corpus...)
Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>Interaction between parkin and mutant glucocerebrosidase variants: a possible link between Parkinson disease and Gaucher disease</title>
<author><name sortKey="Ron, Idit" sort="Ron, Idit" uniqKey="Ron I" first="Idit" last="Ron">Idit Ron</name>
</author>
<author><name sortKey="Rapaport, Debora" sort="Rapaport, Debora" uniqKey="Rapaport D" first="Debora" last="Rapaport">Debora Rapaport</name>
</author>
<author><name sortKey="Horowitz, Mia" sort="Horowitz, Mia" uniqKey="Horowitz M" first="Mia" last="Horowitz">Mia Horowitz</name>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">ISTEX</idno>
<idno type="RBID">ISTEX:DFCD6D29A6F515B59DC5C28FC5D060444D6D8514</idno>
<date when="2010" year="2010">2010</date>
<idno type="doi">10.1093/hmg/ddq292</idno>
<idno type="url">https://api.istex.fr/document/DFCD6D29A6F515B59DC5C28FC5D060444D6D8514/fulltext/pdf</idno>
<idno type="wicri:Area/Main/Corpus">000697</idno>
<idno type="wicri:Area/Main/Curation">000610</idno>
<idno type="wicri:Area/Main/Exploration">000459</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title level="a">Interaction between parkin and mutant glucocerebrosidase variants: a possible link between Parkinson disease and Gaucher disease</title>
<author><name sortKey="Ron, Idit" sort="Ron, Idit" uniqKey="Ron I" first="Idit" last="Ron">Idit Ron</name>
<affiliation wicri:level="1"><country xml:lang="fr">Israël</country>
<wicri:regionArea>Department of Cell Research and Immunology, Tel Aviv University, Ramat Aviv 69978</wicri:regionArea>
<wicri:noRegion>Ramat Aviv 69978</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Rapaport, Debora" sort="Rapaport, Debora" uniqKey="Rapaport D" first="Debora" last="Rapaport">Debora Rapaport</name>
<affiliation wicri:level="1"><country xml:lang="fr">Israël</country>
<wicri:regionArea>Department of Cell Research and Immunology, Tel Aviv University, Ramat Aviv 69978</wicri:regionArea>
<wicri:noRegion>Ramat Aviv 69978</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Horowitz, Mia" sort="Horowitz, Mia" uniqKey="Horowitz M" first="Mia" last="Horowitz">Mia Horowitz</name>
<affiliation wicri:level="1"><country wicri:rule="url">Israël</country>
</affiliation>
</author>
</analytic>
<monogr></monogr>
<series><title level="j">Human Molecular Genetics</title>
<idno type="ISSN">0964-6906</idno>
<idno type="eISSN">1460-2083</idno>
<imprint><publisher>Oxford University Press</publisher>
<date type="published" when="2010-10-01">2010-10-01</date>
<biblScope unit="volume">19</biblScope>
<biblScope unit="issue">19</biblScope>
<biblScope unit="page" from="3771">3771</biblScope>
<biblScope unit="page" to="3781">3781</biblScope>
</imprint>
<idno type="ISSN">0964-6906</idno>
</series>
<idno type="istex">DFCD6D29A6F515B59DC5C28FC5D060444D6D8514</idno>
<idno type="DOI">10.1093/hmg/ddq292</idno>
<idno type="href">ddq292.pdf</idno>
<idno type="ArticleID">ddq292</idno>
</biblStruct>
</sourceDesc>
<seriesStmt><idno type="ISSN">0964-6906</idno>
</seriesStmt>
</fileDesc>
<profileDesc><textClass></textClass>
<langUsage><language ident="en">en</language>
</langUsage>
</profileDesc>
</teiHeader>
<front><div type="abstract">Gaucher disease (GD), a sphingolipidosis characterized by impaired activity of the lysosomal enzyme glucocerebrosidase (GCase), results from mutations in the GCase-encoding gene, GBA. We have shown that mutant GCase variants present variable degrees of endoplasmic reticulum (ER) retention and undergo ER-associated degradation (ERAD) in the proteasome. Furthermore, the degree of ERAD of mutant GCase variants correlates with and is one of the factors that determine GD severity. An association between GD and Parkinson disease (PD) has been demonstrated by the concurrence of PD in GD patients and the identification of GCase mutations in probands with sporadic PD. One of the genes involved in PD is PARK2, encoding the E3 ubiquitin ligase parkin. Parkin functions in the ERAD of misfolded ER proteins, and it is upregulated by unfolded protein response. Loss of parkin function leads to the accumulation of its substrates, which is deleterious to dopaminergic neurons in PD. We, therefore, tested the possibility that the association between GD and PD reflects the fact that parkin acts as an E3 ligase of mutant GCase variants. Our results showed that mutant GCase variants associate with parkin. Normal parkin, but not its RING finger mutants, affects the stability of mutant GCase variants. Parkin also promotes the accumulation of mutant GCase in aggresome-like structures and is involved in K48-mediated polyubiquitination of GCase mutants, indicating its function as its E3 ligase. We suggest that involvement of parkin in the degradation of mutant GCase explains the concurrence of GD and PD.</div>
</front>
</TEI>
<affiliations><list><country><li>Israël</li>
</country>
</list>
<tree><country name="Israël"><noRegion><name sortKey="Ron, Idit" sort="Ron, Idit" uniqKey="Ron I" first="Idit" last="Ron">Idit Ron</name>
</noRegion>
<name sortKey="Horowitz, Mia" sort="Horowitz, Mia" uniqKey="Horowitz M" first="Mia" last="Horowitz">Mia Horowitz</name>
<name sortKey="Rapaport, Debora" sort="Rapaport, Debora" uniqKey="Rapaport D" first="Debora" last="Rapaport">Debora Rapaport</name>
</country>
</tree>
</affiliations>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/ParkinsonV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000459 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000459 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Wicri/Sante |area= ParkinsonV1 |flux= Main |étape= Exploration |type= RBID |clé= ISTEX:DFCD6D29A6F515B59DC5C28FC5D060444D6D8514 |texte= Interaction between parkin and mutant glucocerebrosidase variants: a possible link between Parkinson disease and Gaucher disease }}
This area was generated with Dilib version V0.6.23. |