Treatment with Trehalose Prevents Behavioral and Neurochemical Deficits Produced in an AAV α-Synuclein Rat Model of Parkinson's Disease.
Identifieur interne : 000153 ( Main/Exploration ); précédent : 000152; suivant : 000154Treatment with Trehalose Prevents Behavioral and Neurochemical Deficits Produced in an AAV α-Synuclein Rat Model of Parkinson's Disease.
Auteurs : Qing He [République populaire de Chine] ; James B. Koprich [Canada] ; Ying Wang [République populaire de Chine] ; Wen-Bo Yu [République populaire de Chine] ; Bao-Guo Xiao [République populaire de Chine] ; Jonathan M. Brotchie [Canada] ; Jian Wang [République populaire de Chine]Source :
- Molecular neurobiology [ 1559-1182 ] ; 2016.
English descriptors
- KwdEn :
- Animals, Autophagy (drug effects), Behavior, Animal (drug effects), Blood Glucose (metabolism), Cattle, Cell Survival (drug effects), Dependovirus (metabolism), Disease Models, Animal, Dopaminergic Neurons (drug effects), Dopaminergic Neurons (pathology), Extremities (pathology), Female, Humans, Microtubule-Associated Proteins (metabolism), Parkinson Disease (blood), Parkinson Disease (drug therapy), Parkinson Disease (metabolism), Rats, Sprague-Dawley, Solubility, Substantia Nigra (drug effects), Substantia Nigra (pathology), Trehalose (pharmacology), Trehalose (therapeutic use), Tyrosine 3-Monooxygenase (metabolism), alpha-Synuclein (metabolism).
- MESH :
- chemical , metabolism : Blood Glucose, Microtubule-Associated Proteins, Tyrosine 3-Monooxygenase, alpha-Synuclein.
- blood : Parkinson Disease.
- drug effects : Autophagy, Behavior, Animal, Cell Survival, Dopaminergic Neurons, Substantia Nigra.
- drug therapy : Parkinson Disease.
- metabolism : Dependovirus, Parkinson Disease.
- pathology : Dopaminergic Neurons, Extremities, Substantia Nigra.
- chemical , pharmacology : Trehalose.
- chemical , therapeutic use : Trehalose.
- Animals, Cattle, Disease Models, Animal, Female, Humans, Rats, Sprague-Dawley, Solubility.
Abstract
The accumulation of misfolded α-synuclein in dopamine (DA) neurons is believed to be of major importance in the pathogenesis of Parkinson's disease (PD). Animal models of PD, based on viral-vector-mediated over-expression of α-synuclein, have been developed and show evidence of dopaminergic toxicity, providing us a good tool to investigate potential therapies to interfere with α-synuclein-mediated pathology. An efficient disease-modifying therapeutic molecule should be able to interfere with the neurotoxicity of α-synuclein aggregation. Our study highlighted the ability of an autophagy enhancer, trehalose (at concentrations of 5 and 2% in drinking water), to protect against A53T α-synuclein-mediated DA degeneration in an adeno-associated virus serotype 1/2 (AAV1/2)-based rat model of PD. Behavioral tests and neurochemical analysis demonstrated a significant attenuation in α-synuclein-mediated deficits in motor asymmetry and DA neurodegeneration including impaired DA neuronal survival and DA turnover, as well as α-synuclein accumulation and aggregation in the nigrostriatal system by commencing 5 and 2% trehalose at the same time as delivery of AAV. Trehalose (0.5%) was ineffective on the above behavioral and neurochemical deficits. Further investigation showed that trehalose enhanced autophagy in the striatum by increasing formation of LC3-II. This study supports the concept of using trehalose as a novel therapeutic strategy that might prevent/reverse α-synuclein aggregation for the treatment of PD.
DOI: 10.1007/s12035-015-9173-7
PubMed: 25972237
Affiliations:
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Koprich</name><affiliation wicri:level="1"><nlm:affiliation>Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Wang, Ying" sort="Wang, Ying" uniqKey="Wang Y" first="Ying" last="Wang">Ying Wang</name><affiliation wicri:level="1"><nlm:affiliation>Department & Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, 200040, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department & Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, 200040</wicri:regionArea><wicri:noRegion>200040</wicri:noRegion></affiliation></author><author><name sortKey="Yu, Wen Bo" sort="Yu, Wen Bo" uniqKey="Yu W" first="Wen-Bo" last="Yu">Wen-Bo Yu</name><affiliation wicri:level="1"><nlm:affiliation>Department & Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, 200040, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department & Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, 200040</wicri:regionArea><wicri:noRegion>200040</wicri:noRegion></affiliation></author><author><name sortKey="Xiao, Bao Guo" sort="Xiao, Bao Guo" uniqKey="Xiao B" first="Bao-Guo" last="Xiao">Bao-Guo Xiao</name><affiliation wicri:level="1"><nlm:affiliation>Department & Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, 200040, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department & Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, 200040</wicri:regionArea><wicri:noRegion>200040</wicri:noRegion></affiliation></author><author><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M" last="Brotchie">Jonathan M. Brotchie</name><affiliation wicri:level="1"><nlm:affiliation>Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada. brotchie@uhnres.utoronto.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Wang, Jian" sort="Wang, Jian" uniqKey="Wang J" first="Jian" last="Wang">Jian Wang</name><affiliation wicri:level="1"><nlm:affiliation>Department & Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, 200040, China. wangjian336@hotmail.com.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department & Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, 200040</wicri:regionArea><wicri:noRegion>200040</wicri:noRegion></affiliation></author></analytic><series><title level="j">Molecular neurobiology</title><idno type="eISSN">1559-1182</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Autophagy (drug effects)</term><term>Behavior, Animal (drug effects)</term><term>Blood Glucose (metabolism)</term><term>Cattle</term><term>Cell Survival (drug effects)</term><term>Dependovirus (metabolism)</term><term>Disease Models, Animal</term><term>Dopaminergic Neurons (drug effects)</term><term>Dopaminergic Neurons (pathology)</term><term>Extremities (pathology)</term><term>Female</term><term>Humans</term><term>Microtubule-Associated Proteins (metabolism)</term><term>Parkinson Disease (blood)</term><term>Parkinson Disease (drug therapy)</term><term>Parkinson Disease (metabolism)</term><term>Rats, Sprague-Dawley</term><term>Solubility</term><term>Substantia Nigra (drug effects)</term><term>Substantia Nigra (pathology)</term><term>Trehalose (pharmacology)</term><term>Trehalose (therapeutic use)</term><term>Tyrosine 3-Monooxygenase (metabolism)</term><term>alpha-Synuclein (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Blood Glucose</term><term>Microtubule-Associated Proteins</term><term>Tyrosine 3-Monooxygenase</term><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" qualifier="blood" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Autophagy</term><term>Behavior, Animal</term><term>Cell Survival</term><term>Dopaminergic Neurons</term><term>Substantia Nigra</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Dependovirus</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Dopaminergic Neurons</term><term>Extremities</term><term>Substantia Nigra</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Trehalose</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Trehalose</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cattle</term><term>Disease Models, Animal</term><term>Female</term><term>Humans</term><term>Rats, Sprague-Dawley</term><term>Solubility</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The accumulation of misfolded α-synuclein in dopamine (DA) neurons is believed to be of major importance in the pathogenesis of Parkinson's disease (PD). Animal models of PD, based on viral-vector-mediated over-expression of α-synuclein, have been developed and show evidence of dopaminergic toxicity, providing us a good tool to investigate potential therapies to interfere with α-synuclein-mediated pathology. An efficient disease-modifying therapeutic molecule should be able to interfere with the neurotoxicity of α-synuclein aggregation. Our study highlighted the ability of an autophagy enhancer, trehalose (at concentrations of 5 and 2% in drinking water), to protect against A53T α-synuclein-mediated DA degeneration in an adeno-associated virus serotype 1/2 (AAV1/2)-based rat model of PD. Behavioral tests and neurochemical analysis demonstrated a significant attenuation in α-synuclein-mediated deficits in motor asymmetry and DA neurodegeneration including impaired DA neuronal survival and DA turnover, as well as α-synuclein accumulation and aggregation in the nigrostriatal system by commencing 5 and 2% trehalose at the same time as delivery of AAV. Trehalose (0.5%) was ineffective on the above behavioral and neurochemical deficits. Further investigation showed that trehalose enhanced autophagy in the striatum by increasing formation of LC3-II. This study supports the concept of using trehalose as a novel therapeutic strategy that might prevent/reverse α-synuclein aggregation for the treatment of PD.</div></front></TEI><affiliations><list><country><li>Canada</li><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="He, Qing" sort="He, Qing" uniqKey="He Q" first="Qing" last="He">Qing He</name></noRegion><name sortKey="Wang, Jian" sort="Wang, Jian" uniqKey="Wang J" first="Jian" last="Wang">Jian Wang</name><name sortKey="Wang, Ying" sort="Wang, Ying" uniqKey="Wang Y" first="Ying" last="Wang">Ying Wang</name><name sortKey="Xiao, Bao Guo" sort="Xiao, Bao Guo" uniqKey="Xiao B" first="Bao-Guo" last="Xiao">Bao-Guo Xiao</name><name sortKey="Yu, Wen Bo" sort="Yu, Wen Bo" uniqKey="Yu W" first="Wen-Bo" last="Yu">Wen-Bo Yu</name></country><country name="Canada"><noRegion><name sortKey="Koprich, James B" sort="Koprich, James B" uniqKey="Koprich J" first="James B" last="Koprich">James B. Koprich</name></noRegion><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M" last="Brotchie">Jonathan M. Brotchie</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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