A one-hit model of cell death in inherited neuronal degenerations
Identifieur interne : 000038 ( PascalFrancis/Curation ); précédent : 000037; suivant : 000039A one-hit model of cell death in inherited neuronal degenerations
Auteurs : G. Clarke [Canada] ; R. A. Collins [Canada] ; B. R. Leavitt [Canada] ; D. F. Andrews [Canada] ; M. R. Hayden [Canada] ; C. J. Lumsden [Canada] ; R. R. Mcinnes [Canada]Source :
- Nature : (London) [ 0028-0836 ] ; 2000.
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- Pascal (Inist)
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Abstract
In genetic disorders associated with premature neuronal death, symptoms may not appear for years or decades. This delay in clinical onset is often assumed to reflect the occurrence of age-dependent cumulative damage1-6. For example, it has been suggested that oxidative stress disrupts metabolism in neurological degenerative disorders by the cumulative damage of essential macromolecules1,4,7. A prediction of the cumulative damage hypothesis is that the probability of cell death will increase over time. Here we show in contrast that the kinetics of neuronal death in 12 models of photoreceptor degeneration, hippocampal neurons undergoing excitotoxic cell deaths, a mouse model of cerebellar degeneration9 and Parkinson's10 and Huntington's diseases are all exponential and better explained by mathematical models in which the risk of cell death remains constant or decreases exponentially with age. These kinetics argue against the cumulative damage hypothesis; instead, the time of death of any neuron is random. Our findings are most simply accommodated by a 'one-hit' biochemical model in which mutation imposes a mutant steady state on the neuron and a single event randomly initiates cell death. This model appears to be common to many forms of neurodegeneration and has implications for therapeutic strategies.
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A." last="Collins">R. A. Collins</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Molecular and Medical Genetics, Institute of Medical Science, University of Toronto, 1 King's College Circle</s1><s2>Toronto, Ontario M5S 1A8</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Canada</country></affiliation></author><author><name sortKey="Leavitt, B R" sort="Leavitt, B R" uniqKey="Leavitt B" first="B. R." last="Leavitt">B. R. Leavitt</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics University of British Columbia</s1><s2>Vancouver, British Columbia V5Z 4H4</s2><s3>CAN</s3><sZ>3 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Canada</country></affiliation></author><author><name sortKey="Andrews, D F" sort="Andrews, D F" uniqKey="Andrews D" first="D. F." last="Andrews">D. F. 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Clarke</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Programs in Developmental Biology and Genetics, The Research Institute, Hospital for Sick Children, 555 University Ave.</s1><s2>Toronto, Ontario M5G 1X8</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Canada</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Molecular and Medical Genetics, Institute of Medical Science, University of Toronto, 1 King's College Circle</s1><s2>Toronto, Ontario M5S 1A8</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Canada</country></affiliation></author><author><name sortKey="Collins, R A" sort="Collins, R A" uniqKey="Collins R" first="R. A." last="Collins">R. A. Collins</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Molecular and Medical Genetics, Institute of Medical Science, University of Toronto, 1 King's College Circle</s1><s2>Toronto, Ontario M5S 1A8</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Canada</country></affiliation></author><author><name sortKey="Leavitt, B R" sort="Leavitt, B R" uniqKey="Leavitt B" first="B. R." last="Leavitt">B. R. Leavitt</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics University of British Columbia</s1><s2>Vancouver, British Columbia V5Z 4H4</s2><s3>CAN</s3><sZ>3 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Canada</country></affiliation></author><author><name sortKey="Andrews, D F" sort="Andrews, D F" uniqKey="Andrews D" first="D. F." last="Andrews">D. F. Andrews</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Department of Statistics, University of Toronto, 100 St. George Street</s1><s2>M5S 3G3</s2><s3>CAN</s3><sZ>4 aut.</sZ></inist:fA14><country>Canada</country></affiliation></author><author><name sortKey="Hayden, M R" sort="Hayden, M R" uniqKey="Hayden M" first="M. R." last="Hayden">M. R. Hayden</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics University of British Columbia</s1><s2>Vancouver, British Columbia V5Z 4H4</s2><s3>CAN</s3><sZ>3 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Canada</country></affiliation></author><author><name sortKey="Lumsden, C J" sort="Lumsden, C J" uniqKey="Lumsden C" first="C. J." last="Lumsden">C. J. Lumsden</name><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Department of Medicine, Institute of Medical Science, University of Toronto, 1 King's College Circle</s1><s2>Toronto, Ontario M5S 1A8</s2><s3>CAN</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Canada</country></affiliation></author><author><name sortKey="Mcinnes, R R" sort="Mcinnes, R R" uniqKey="Mcinnes R" first="R. R." last="Mcinnes">R. R. Mcinnes</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Programs in Developmental Biology and Genetics, The Research Institute, Hospital for Sick Children, 555 University Ave.</s1><s2>Toronto, Ontario M5G 1X8</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Canada</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Molecular and Medical Genetics, Institute of Medical Science, University of Toronto, 1 King's College Circle</s1><s2>Toronto, Ontario M5S 1A8</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Canada</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Department of Medicine, Institute of Medical Science, University of Toronto, 1 King's College Circle</s1><s2>Toronto, Ontario M5S 1A8</s2><s3>CAN</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Canada</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Department of Pediatrics, Institute of Medical Science, University of Toronto, 1 King's College Circle</s1><s2>Toronto, Ontario M5S 1A8</s2><s3>CAN</s3><sZ>7 aut.</sZ></inist:fA14><country>Canada</country></affiliation></author></analytic><series><title level="j" type="main">Nature : (London)</title><title level="j" type="abbreviated">Nature : (Lond.)</title><idno type="ISSN">0028-0836</idno><imprint><date when="2000">2000</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Nature : (London)</title><title level="j" type="abbreviated">Nature : (Lond.)</title><idno type="ISSN">0028-0836</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cell death</term><term>Degeneration</term><term>Models</term><term>Neuron</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Mort cellulaire</term><term>Neurone</term><term>Dégénérescence</term><term>Modèle</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">In genetic disorders associated with premature neuronal death, symptoms may not appear for years or decades. This delay in clinical onset is often assumed to reflect the occurrence of age-dependent cumulative damage<sup>1-6</sup>. For example, it has been suggested that oxidative stress disrupts metabolism in neurological degenerative disorders by the cumulative damage of essential macromolecules<sup>1,4,7</sup>. A prediction of the cumulative damage hypothesis is that the probability of cell death will increase over time. Here we show in contrast that the kinetics of neuronal death in 12 models of photoreceptor degeneration, hippocampal neurons undergoing excitotoxic cell deaths, a mouse model of cerebellar degeneration<sup>9</sup> and Parkinson's<sup>10</sup> and Huntington's diseases are all exponential and better explained by mathematical models in which the risk of cell death remains constant or decreases exponentially with age. These kinetics argue against the cumulative damage hypothesis; instead, the time of death of any neuron is random. Our findings are most simply accommodated by a 'one-hit' biochemical model in which mutation imposes a mutant steady state on the neuron and a single event randomly initiates cell death. This model appears to be common to many forms of neurodegeneration and has implications for therapeutic strategies.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0028-0836</s0></fA01><fA02 i1="01"><s0>NATUAS</s0></fA02><fA03 i2="1"><s0>Nature : (Lond.)</s0></fA03><fA05><s2>406</s2></fA05><fA06><s2>6792</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>A one-hit model of cell death in inherited neuronal degenerations</s1></fA08><fA11 i1="01" i2="1"><s1>CLARKE (G.)</s1></fA11><fA11 i1="02" i2="1"><s1>COLLINS (R. A.)</s1></fA11><fA11 i1="03" i2="1"><s1>LEAVITT (B. R.)</s1></fA11><fA11 i1="04" i2="1"><s1>ANDREWS (D. F.)</s1></fA11><fA11 i1="05" i2="1"><s1>HAYDEN (M. R.)</s1></fA11><fA11 i1="06" i2="1"><s1>LUMSDEN (C. J.)</s1></fA11><fA11 i1="07" i2="1"><s1>MCINNES (R. R.)</s1></fA11><fA14 i1="01"><s1>Programs in Developmental Biology and Genetics, The Research Institute, Hospital for Sick Children, 555 University Ave.</s1><s2>Toronto, Ontario M5G 1X8</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ></fA14><fA14 i1="02"><s1>Department of Molecular and Medical Genetics, Institute of Medical Science, University of Toronto, 1 King's College Circle</s1><s2>Toronto, Ontario M5S 1A8</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>7 aut.</sZ></fA14><fA14 i1="03"><s1>Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics University of British Columbia</s1><s2>Vancouver, British Columbia V5Z 4H4</s2><s3>CAN</s3><sZ>3 aut.</sZ><sZ>5 aut.</sZ></fA14><fA14 i1="04"><s1>Department of Statistics, University of Toronto, 100 St. George Street</s1><s2>M5S 3G3</s2><s3>CAN</s3><sZ>4 aut.</sZ></fA14><fA14 i1="05"><s1>Department of Medicine, Institute of Medical Science, University of Toronto, 1 King's College Circle</s1><s2>Toronto, Ontario M5S 1A8</s2><s3>CAN</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></fA14><fA14 i1="06"><s1>Department of Pediatrics, Institute of Medical Science, University of Toronto, 1 King's College Circle</s1><s2>Toronto, Ontario M5S 1A8</s2><s3>CAN</s3><sZ>7 aut.</sZ></fA14><fA20><s1>195-199</s1></fA20><fA21><s1>2000</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>142</s2><s5>354000090492230290</s5></fA43><fA44><s0>0000</s0><s1>© 2000 INIST-CNRS. 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Here we show in contrast that the kinetics of neuronal death in 12 models of photoreceptor degeneration, hippocampal neurons undergoing excitotoxic cell deaths, a mouse model of cerebellar degeneration<sup>9</sup> and Parkinson's<sup>10</sup> and Huntington's diseases are all exponential and better explained by mathematical models in which the risk of cell death remains constant or decreases exponentially with age. These kinetics argue against the cumulative damage hypothesis; instead, the time of death of any neuron is random. Our findings are most simply accommodated by a 'one-hit' biochemical model in which mutation imposes a mutant steady state on the neuron and a single event randomly initiates cell death. 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