Mitochondrial dysfunction precedes other sub-cellular abnormalities in an in vitro model linked with cell death in Parkinson's disease.
Identifieur interne : 000A36 ( PubMed/Checkpoint ); précédent : 000A35; suivant : 000A37Mitochondrial dysfunction precedes other sub-cellular abnormalities in an in vitro model linked with cell death in Parkinson's disease.
Auteurs : C J Yong-Kee [Canada] ; E. Sidorova ; A. Hanif ; G. Perera ; J E NashSource :
- Neurotoxicity research [ 1476-3524 ] ; 2012.
English descriptors
- KwdEn :
- Cell Death (drug effects), Cell Line, Tumor, Humans, Lysosomes (drug effects), Mitochondria (drug effects), Mitochondria (metabolism), Naphthoquinones (toxicity), Neurons (drug effects), Neurons (metabolism), Parkinson Disease, Secondary (chemically induced), Proteasome Endopeptidase Complex (drug effects), Rotenone (toxicity), Time Factors, Ubiquitin (drug effects).
- MESH :
- chemical , drug effects : Proteasome Endopeptidase Complex, Ubiquitin.
- chemical , toxicity : Naphthoquinones, Rotenone.
- chemically induced : Parkinson Disease, Secondary.
- drug effects : Cell Death, Lysosomes, Mitochondria, Neurons.
- metabolism : Mitochondria, Neurons.
- Cell Line, Tumor, Humans, Time Factors.
Abstract
Dysfunction of mitochondria, the ubiquitin proteasome system (UPS), and lysosomes are believed to contribute to the pathogenesis of Parkinson's disease (PD). If it were possible to rescue functionally compromised, but still viable neurons early in the disease process, this would slow the rate of neurodegeneration. Here, we used a catecholaminergic neuroblastoma cell line (SH-SY5Y) as a model of susceptible neurons in PD. To identify a target early in the cell death process that was common to all neurodegenerative processes linked with PD, cells were exposed to toxins that mimic cell death mechanisms associated with PD. The sub-cellular abnormalities that occur shortly after toxin exposure were determined. 3 h of exposure to either naphthazarin, to inhibit lysosomal function, Z-Ile-Glu(OBu(t))-Ala-Leu-H (PSI), to inhibit the UPS, or rotenone, to inhibit mitochondrial complex I, caused depolarisation of the mitochondrial membrane potential (2.5-fold, twofold, and 4.6-fold change, respectively compared to vehicle), suggesting impaired mitochondrial function. Following 24 h exposure to the same toxins, UPS and lysosomal function were also impaired, and ubiquitin levels were increased. Thus, following exposure to toxins that mimic three important, but disparate cell death mechanisms associated with PD, catecholaminergic cells initially experience mitochondrial dysfunction, which is then followed by abnormalities in UPS and lysosomal function. Thus, mitochondrial dysfunction is an early event in cell stress. We suggest that, in patients with PD, the surviving cells of the substantia nigra pars compacta are most susceptible to mitochondrial impairment. Thus, targeting the mitochondria may be useful for slowing the progression of neurodegeneration in PD.
DOI: 10.1007/s12640-011-9259-6
PubMed: 21773851
Affiliations:
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Sidorova</name></author><author><name sortKey="Hanif, A" sort="Hanif, A" uniqKey="Hanif A" first="A" last="Hanif">A. Hanif</name></author><author><name sortKey="Perera, G" sort="Perera, G" uniqKey="Perera G" first="G" last="Perera">G. 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If it were possible to rescue functionally compromised, but still viable neurons early in the disease process, this would slow the rate of neurodegeneration. Here, we used a catecholaminergic neuroblastoma cell line (SH-SY5Y) as a model of susceptible neurons in PD. To identify a target early in the cell death process that was common to all neurodegenerative processes linked with PD, cells were exposed to toxins that mimic cell death mechanisms associated with PD. The sub-cellular abnormalities that occur shortly after toxin exposure were determined. 3 h of exposure to either naphthazarin, to inhibit lysosomal function, Z-Ile-Glu(OBu(t))-Ala-Leu-H (PSI), to inhibit the UPS, or rotenone, to inhibit mitochondrial complex I, caused depolarisation of the mitochondrial membrane potential (2.5-fold, twofold, and 4.6-fold change, respectively compared to vehicle), suggesting impaired mitochondrial function. Following 24 h exposure to the same toxins, UPS and lysosomal function were also impaired, and ubiquitin levels were increased. Thus, following exposure to toxins that mimic three important, but disparate cell death mechanisms associated with PD, catecholaminergic cells initially experience mitochondrial dysfunction, which is then followed by abnormalities in UPS and lysosomal function. Thus, mitochondrial dysfunction is an early event in cell stress. We suggest that, in patients with PD, the surviving cells of the substantia nigra pars compacta are most susceptible to mitochondrial impairment. Thus, targeting the mitochondria may be useful for slowing the progression of neurodegeneration in PD.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">21773851</PMID><DateCreated><Year>2011</Year><Month>12</Month><Day>28</Day></DateCreated><DateCompleted><Year>2012</Year><Month>04</Month><Day>17</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1476-3524</ISSN><JournalIssue CitedMedium="Internet"><Volume>21</Volume><Issue>2</Issue><PubDate><Year>2012</Year><Month>Feb</Month></PubDate></JournalIssue><Title>Neurotoxicity research</Title><ISOAbbreviation>Neurotox Res</ISOAbbreviation></Journal><ArticleTitle>Mitochondrial dysfunction precedes other sub-cellular abnormalities in an in vitro model linked with cell death in Parkinson's disease.</ArticleTitle><Pagination><MedlinePgn>185-94</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1007/s12640-011-9259-6</ELocationID><Abstract><AbstractText>Dysfunction of mitochondria, the ubiquitin proteasome system (UPS), and lysosomes are believed to contribute to the pathogenesis of Parkinson's disease (PD). If it were possible to rescue functionally compromised, but still viable neurons early in the disease process, this would slow the rate of neurodegeneration. Here, we used a catecholaminergic neuroblastoma cell line (SH-SY5Y) as a model of susceptible neurons in PD. To identify a target early in the cell death process that was common to all neurodegenerative processes linked with PD, cells were exposed to toxins that mimic cell death mechanisms associated with PD. The sub-cellular abnormalities that occur shortly after toxin exposure were determined. 3 h of exposure to either naphthazarin, to inhibit lysosomal function, Z-Ile-Glu(OBu(t))-Ala-Leu-H (PSI), to inhibit the UPS, or rotenone, to inhibit mitochondrial complex I, caused depolarisation of the mitochondrial membrane potential (2.5-fold, twofold, and 4.6-fold change, respectively compared to vehicle), suggesting impaired mitochondrial function. Following 24 h exposure to the same toxins, UPS and lysosomal function were also impaired, and ubiquitin levels were increased. Thus, following exposure to toxins that mimic three important, but disparate cell death mechanisms associated with PD, catecholaminergic cells initially experience mitochondrial dysfunction, which is then followed by abnormalities in UPS and lysosomal function. Thus, mitochondrial dysfunction is an early event in cell stress. We suggest that, in patients with PD, the surviving cells of the substantia nigra pars compacta are most susceptible to mitochondrial impairment. 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PubStatus="medline"><Year>2012</Year><Month>4</Month><Day>18</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">21773851</ArticleId><ArticleId IdType="doi">10.1007/s12640-011-9259-6</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Canada</li></country></list><tree><noCountry><name sortKey="Hanif, A" sort="Hanif, A" uniqKey="Hanif A" first="A" last="Hanif">A. Hanif</name><name sortKey="Nash, J E" sort="Nash, J E" uniqKey="Nash J" first="J E" last="Nash">J E Nash</name><name sortKey="Perera, G" sort="Perera, G" uniqKey="Perera G" first="G" last="Perera">G. Perera</name><name sortKey="Sidorova, E" sort="Sidorova, E" uniqKey="Sidorova E" first="E" last="Sidorova">E. Sidorova</name></noCountry><country name="Canada"><noRegion><name sortKey="Yong Kee, C J" sort="Yong Kee, C J" uniqKey="Yong Kee C" first="C J" last="Yong-Kee">C J Yong-Kee</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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