DJ-1 deficient mice demonstrate similar vulnerability to pathogenic Ala53Thr human -syn toxicity
Identifieur interne : 000474 ( Main/Exploration ); précédent : 000473; suivant : 000475DJ-1 deficient mice demonstrate similar vulnerability to pathogenic Ala53Thr human -syn toxicity
Auteurs : Chenere P. Ramsey ; Elpida Tsika ; Harry Ischiropoulos ; Benoit I. Giasson [États-Unis]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-04-15.
Abstract
Parkinson's disease (PD) is the most common neurodegenerative movement disorder. A pathological hallmark of PD is the presence of intraneuronal inclusions composed of fibrillized -synuclein (-syn) in affected brain regions. Mutations in the gene, PARK7, which encodes DJ-1, can cause autosomal recessive early-onset PD. Although DJ-1 has been shown to be involved in diverse biological processes, several in vitro studies suggest that it can inhibit the formation and protect against the effects of -syn aggregation. We previously established and characterized transgenic mice expressing pathogenic Ala53Thr human -syn (M83 mice) that develop extensive -syn pathologies in the neuroaxis resulting in severe motor impairments and eventual fatality. In the current study, we have crossbred M83 mice on a DJ-1 null background (M83-DJnull mice) in efforts to determine the effects of the lack of DJ-1 in these mice. Animals were assessed and compared for survival rate, distribution of -syn inclusions, biochemical properties of -syn protein, demise and function of nigral dopaminergic neurons, and extent of gliosis in the neuroaxis. M83 and M83-DJnull mice displayed a similar onset of disease and pathological changes, and none of the analyses to assess for changes in pathogenesis revealed any significant differences between M83 and M83-DJnull mice. These findings suggest that DJ-1 may not function to directly modulate -syn nor does DJ-1 appear to play a role in protecting against the deleterious effects of expressing pathogenic Ala53Thr -syn in vivo. It is possible that -syn and DJ-1 mutations may lead to PD via independent mechanisms.
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DOI: 10.1093/hmg/ddq017
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Giasson</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation><affiliation wicri:level="1"><country wicri:rule="url">États-Unis</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="2010-04-15">2010-04-15</date><biblScope unit="volume">19</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="1425">1425</biblScope><biblScope unit="page" to="1437">1437</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">3F93A9736418869E62A5E8211A68D079540B726F</idno><idno type="DOI">10.1093/hmg/ddq017</idno><idno type="ArticleID">ddq017</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">Parkinson's disease (PD) is the most common neurodegenerative movement disorder. A pathological hallmark of PD is the presence of intraneuronal inclusions composed of fibrillized -synuclein (-syn) in affected brain regions. Mutations in the gene, PARK7, which encodes DJ-1, can cause autosomal recessive early-onset PD. Although DJ-1 has been shown to be involved in diverse biological processes, several in vitro studies suggest that it can inhibit the formation and protect against the effects of -syn aggregation. We previously established and characterized transgenic mice expressing pathogenic Ala53Thr human -syn (M83 mice) that develop extensive -syn pathologies in the neuroaxis resulting in severe motor impairments and eventual fatality. In the current study, we have crossbred M83 mice on a DJ-1 null background (M83-DJnull mice) in efforts to determine the effects of the lack of DJ-1 in these mice. Animals were assessed and compared for survival rate, distribution of -syn inclusions, biochemical properties of -syn protein, demise and function of nigral dopaminergic neurons, and extent of gliosis in the neuroaxis. M83 and M83-DJnull mice displayed a similar onset of disease and pathological changes, and none of the analyses to assess for changes in pathogenesis revealed any significant differences between M83 and M83-DJnull mice. These findings suggest that DJ-1 may not function to directly modulate -syn nor does DJ-1 appear to play a role in protecting against the deleterious effects of expressing pathogenic Ala53Thr -syn in vivo. It is possible that -syn and DJ-1 mutations may lead to PD via independent mechanisms.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><noCountry><name sortKey="Ischiropoulos, Harry" sort="Ischiropoulos, Harry" uniqKey="Ischiropoulos H" first="Harry" last="Ischiropoulos">Harry Ischiropoulos</name><name sortKey="Ramsey, Chenere P" sort="Ramsey, Chenere P" uniqKey="Ramsey C" first="Chenere P." last="Ramsey">Chenere P. Ramsey</name><name sortKey="Tsika, Elpida" sort="Tsika, Elpida" uniqKey="Tsika E" first="Elpida" last="Tsika">Elpida Tsika</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Giasson, Benoit I" sort="Giasson, Benoit I" uniqKey="Giasson B" first="Benoit I." last="Giasson">Benoit I. Giasson</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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