Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease.
Identifieur interne : 000443 ( PubMed/Corpus ); précédent : 000442; suivant : 000444Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease.
Auteurs : Ulrika Nordström ; Geneviève Beauvais ; Anamitra Ghosh ; Baby Chakrapani Pulikkaparambil Sasidharan ; Martin Lundblad ; Julia Fuchs ; Rajiv L. Joshi ; Jack W. Lipton ; Andrew Roholt ; Satish Medicetty ; Timothy N. Feinstein ; Jennifer A. Steiner ; Martha L. Escobar Galvis ; Alain Prochiantz ; Patrik BrundinSource :
- Neurobiology of disease [ 1095-953X ] ; 2015.
English descriptors
- KwdEn :
- 3,4-Dihydroxyphenylacetic Acid (metabolism), Animals, Autophagy (genetics), Corpus Striatum (metabolism), Corpus Striatum (pathology), Disease Models, Animal, Disease Progression, Dopaminergic Neurons (metabolism), Dopaminergic Neurons (pathology), Dopaminergic Neurons (ultrastructure), Gene Expression Regulation (genetics), Green Fluorescent Proteins (genetics), Green Fluorescent Proteins (metabolism), Homeodomain Proteins (genetics), Homovanillic Acid (metabolism), Mice, Mice, Transgenic, Nerve Degeneration (etiology), Parkinson Disease (complications), Parkinson Disease (genetics), Parkinson Disease (pathology), Signal Transduction (drug effects), Signal Transduction (genetics), Substantia Nigra (metabolism), Substantia Nigra (pathology), TOR Serine-Threonine Kinases (metabolism), Time Factors, Tyrosine 3-Monooxygenase (genetics), Tyrosine 3-Monooxygenase (metabolism).
- MESH :
- chemical , genetics : Green Fluorescent Proteins, Homeodomain Proteins, Tyrosine 3-Monooxygenase.
- chemical , metabolism : 3,4-Dihydroxyphenylacetic Acid, Green Fluorescent Proteins, Homovanillic Acid, TOR Serine-Threonine Kinases, Tyrosine 3-Monooxygenase.
- complications : Parkinson Disease.
- drug effects : Signal Transduction.
- etiology : Nerve Degeneration.
- genetics : Autophagy, Gene Expression Regulation, Parkinson Disease, Signal Transduction.
- metabolism : Corpus Striatum, Dopaminergic Neurons, Substantia Nigra.
- pathology : Corpus Striatum, Dopaminergic Neurons, Parkinson Disease, Substantia Nigra.
- ultrastructure : Dopaminergic Neurons.
- Animals, Disease Models, Animal, Disease Progression, Mice, Mice, Transgenic, Time Factors.
Abstract
Current research on Parkinson's disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests that En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1(+/-) mice with a focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1(+/-) mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of the En1(+/-) mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of the En1(+/-) mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely deficient in dopamine release and reuptake. Our findings support a progressive retrograde degeneration of En1(+/-) nigrostriatal neurons, akin to what is suggested to occur in PD. We suggest that using the En1(+/-) mice as a model will provide further key insights into PD pathogenesis, and propose that axon terminal integrity and function can be utilized to estimate dopaminergic neuron health and efficacy of experimental PD therapies.
DOI: 10.1016/j.nbd.2014.09.012
PubMed: 25281317
Links to Exploration step
pubmed:25281317Le document en format XML
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Feinstein</name><affiliation><nlm:affiliation>Confocal Microscopy and Quantitative Imaging Core Facility, Van Andel Research Institute, 333 Bostwick Ave, N.E., Grand Rapids, MI 49503, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Steiner, Jennifer A" sort="Steiner, Jennifer A" uniqKey="Steiner J" first="Jennifer A" last="Steiner">Jennifer A. Steiner</name><affiliation><nlm:affiliation>Laboratory of Translational Parkinson's Disease Research, Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave, N.E., Grand Rapids, MI 49503, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Escobar Galvis, Martha L" sort="Escobar Galvis, Martha L" uniqKey="Escobar Galvis M" first="Martha L" last="Escobar Galvis">Martha L. Escobar Galvis</name><affiliation><nlm:affiliation>Laboratory of Translational Parkinson's Disease Research, Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave, N.E., Grand Rapids, MI 49503, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Prochiantz, Alain" sort="Prochiantz, Alain" uniqKey="Prochiantz A" first="Alain" last="Prochiantz">Alain Prochiantz</name><affiliation><nlm:affiliation>Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, Paris, France; Institut National de la Santé et de la Recherche Médicale U1050, Labex Memolife, Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Brundin, Patrik" sort="Brundin, Patrik" uniqKey="Brundin P" first="Patrik" last="Brundin">Patrik Brundin</name><affiliation><nlm:affiliation>Neuronal Survival Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC B11, 221 84 Lund, Sweden; Laboratory of Translational Parkinson's Disease Research, Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave, N.E., Grand Rapids, MI 49503, USA. 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Joshi</name><affiliation><nlm:affiliation>Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, Paris, France; Institut National de la Santé et de la Recherche Médicale U1050, Labex Memolife, Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Lipton, Jack W" sort="Lipton, Jack W" uniqKey="Lipton J" first="Jack W" last="Lipton">Jack W. Lipton</name><affiliation><nlm:affiliation>Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI 49503, USA; The Udall Center of Excellence in Parkinson's Disease Research, Michigan State University, Grand Rapids, MI 49503, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Roholt, Andrew" sort="Roholt, Andrew" uniqKey="Roholt A" first="Andrew" last="Roholt">Andrew Roholt</name><affiliation><nlm:affiliation>Renovo Neural, Inc., 10000 Cedar Avenue, Cleveland, OH 44106, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Medicetty, Satish" sort="Medicetty, Satish" uniqKey="Medicetty S" first="Satish" last="Medicetty">Satish Medicetty</name><affiliation><nlm:affiliation>Renovo Neural, Inc., 10000 Cedar Avenue, Cleveland, OH 44106, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Feinstein, Timothy N" sort="Feinstein, Timothy N" uniqKey="Feinstein T" first="Timothy N" last="Feinstein">Timothy N. Feinstein</name><affiliation><nlm:affiliation>Confocal Microscopy and Quantitative Imaging Core Facility, Van Andel Research Institute, 333 Bostwick Ave, N.E., Grand Rapids, MI 49503, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Steiner, Jennifer A" sort="Steiner, Jennifer A" uniqKey="Steiner J" first="Jennifer A" last="Steiner">Jennifer A. Steiner</name><affiliation><nlm:affiliation>Laboratory of Translational Parkinson's Disease Research, Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave, N.E., Grand Rapids, MI 49503, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Escobar Galvis, Martha L" sort="Escobar Galvis, Martha L" uniqKey="Escobar Galvis M" first="Martha L" last="Escobar Galvis">Martha L. Escobar Galvis</name><affiliation><nlm:affiliation>Laboratory of Translational Parkinson's Disease Research, Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave, N.E., Grand Rapids, MI 49503, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Prochiantz, Alain" sort="Prochiantz, Alain" uniqKey="Prochiantz A" first="Alain" last="Prochiantz">Alain Prochiantz</name><affiliation><nlm:affiliation>Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, Paris, France; Institut National de la Santé et de la Recherche Médicale U1050, Labex Memolife, Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Brundin, Patrik" sort="Brundin, Patrik" uniqKey="Brundin P" first="Patrik" last="Brundin">Patrik Brundin</name><affiliation><nlm:affiliation>Neuronal Survival Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC B11, 221 84 Lund, Sweden; Laboratory of Translational Parkinson's Disease Research, Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave, N.E., Grand Rapids, MI 49503, USA. Electronic address: Patrik.Brundin@vai.org.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Neurobiology of disease</title><idno type="eISSN">1095-953X</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>3,4-Dihydroxyphenylacetic Acid (metabolism)</term><term>Animals</term><term>Autophagy (genetics)</term><term>Corpus Striatum (metabolism)</term><term>Corpus Striatum (pathology)</term><term>Disease Models, Animal</term><term>Disease Progression</term><term>Dopaminergic Neurons (metabolism)</term><term>Dopaminergic Neurons (pathology)</term><term>Dopaminergic Neurons (ultrastructure)</term><term>Gene Expression Regulation (genetics)</term><term>Green Fluorescent Proteins (genetics)</term><term>Green Fluorescent Proteins (metabolism)</term><term>Homeodomain Proteins (genetics)</term><term>Homovanillic Acid (metabolism)</term><term>Mice</term><term>Mice, Transgenic</term><term>Nerve Degeneration (etiology)</term><term>Parkinson Disease (complications)</term><term>Parkinson Disease (genetics)</term><term>Parkinson Disease (pathology)</term><term>Signal Transduction (drug effects)</term><term>Signal Transduction (genetics)</term><term>Substantia Nigra (metabolism)</term><term>Substantia Nigra (pathology)</term><term>TOR Serine-Threonine Kinases (metabolism)</term><term>Time Factors</term><term>Tyrosine 3-Monooxygenase (genetics)</term><term>Tyrosine 3-Monooxygenase (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Green Fluorescent Proteins</term><term>Homeodomain Proteins</term><term>Tyrosine 3-Monooxygenase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>3,4-Dihydroxyphenylacetic Acid</term><term>Green Fluorescent Proteins</term><term>Homovanillic Acid</term><term>TOR Serine-Threonine Kinases</term><term>Tyrosine 3-Monooxygenase</term></keywords><keywords scheme="MESH" qualifier="complications" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="etiology" xml:lang="en"><term>Nerve Degeneration</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Autophagy</term><term>Gene Expression Regulation</term><term>Parkinson Disease</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Corpus Striatum</term><term>Dopaminergic Neurons</term><term>Substantia Nigra</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Corpus Striatum</term><term>Dopaminergic Neurons</term><term>Parkinson Disease</term><term>Substantia Nigra</term></keywords><keywords scheme="MESH" qualifier="ultrastructure" xml:lang="en"><term>Dopaminergic Neurons</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Disease Models, Animal</term><term>Disease Progression</term><term>Mice</term><term>Mice, Transgenic</term><term>Time Factors</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Current research on Parkinson's disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests that En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1(+/-) mice with a focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1(+/-) mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of the En1(+/-) mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of the En1(+/-) mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely deficient in dopamine release and reuptake. Our findings support a progressive retrograde degeneration of En1(+/-) nigrostriatal neurons, akin to what is suggested to occur in PD. We suggest that using the En1(+/-) mice as a model will provide further key insights into PD pathogenesis, and propose that axon terminal integrity and function can be utilized to estimate dopaminergic neuron health and efficacy of experimental PD therapies.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">25281317</PMID><DateCreated><Year>2014</Year><Month>12</Month><Day>02</Day></DateCreated><DateCompleted><Year>2015</Year><Month>07</Month><Day>29</Day></DateCompleted><DateRevised><Year>2017</Year><Month>01</Month><Day>17</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1095-953X</ISSN><JournalIssue CitedMedium="Internet"><Volume>73</Volume><PubDate><Year>2015</Year><Month>Jan</Month></PubDate></JournalIssue><Title>Neurobiology of disease</Title><ISOAbbreviation>Neurobiol. Dis.</ISOAbbreviation></Journal><ArticleTitle>Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease.</ArticleTitle><Pagination><MedlinePgn>70-82</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.nbd.2014.09.012</ELocationID><ELocationID EIdType="pii" ValidYN="Y">S0969-9961(14)00284-8</ELocationID><Abstract><AbstractText>Current research on Parkinson's disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests that En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1(+/-) mice with a focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1(+/-) mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of the En1(+/-) mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of the En1(+/-) mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely deficient in dopamine release and reuptake. Our findings support a progressive retrograde degeneration of En1(+/-) nigrostriatal neurons, akin to what is suggested to occur in PD. We suggest that using the En1(+/-) mice as a model will provide further key insights into PD pathogenesis, and propose that axon terminal integrity and function can be utilized to estimate dopaminergic neuron health and efficacy of experimental PD therapies.</AbstractText><CopyrightInformation>Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Nordström</LastName><ForeName>Ulrika</ForeName><Initials>U</Initials><AffiliationInfo><Affiliation>Neuronal Survival Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC B11, 221 84 Lund, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Beauvais</LastName><ForeName>Geneviève</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Laboratory of Translational Parkinson's Disease Research, Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave, N.E., Grand Rapids, MI 49503, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ghosh</LastName><ForeName>Anamitra</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Laboratory of Translational Parkinson's Disease Research, Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave, N.E., Grand Rapids, MI 49503, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pulikkaparambil Sasidharan</LastName><ForeName>Baby Chakrapani</ForeName><Initials>BC</Initials><AffiliationInfo><Affiliation>Laboratory of Translational Parkinson's Disease Research, Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave, N.E., Grand Rapids, MI 49503, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lundblad</LastName><ForeName>Martin</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC A11, 221 84 Lund, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fuchs</LastName><ForeName>Julia</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, Paris, France; Institut National de la Santé et de la Recherche Médicale U1050, Labex Memolife, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Joshi</LastName><ForeName>Rajiv L</ForeName><Initials>RL</Initials><AffiliationInfo><Affiliation>Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, Paris, France; Institut National de la Santé et de la Recherche Médicale U1050, Labex Memolife, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lipton</LastName><ForeName>Jack W</ForeName><Initials>JW</Initials><AffiliationInfo><Affiliation>Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI 49503, USA; The Udall Center of Excellence in Parkinson's Disease Research, Michigan State University, Grand Rapids, MI 49503, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Roholt</LastName><ForeName>Andrew</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Renovo Neural, Inc., 10000 Cedar Avenue, Cleveland, OH 44106, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Medicetty</LastName><ForeName>Satish</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Renovo Neural, Inc., 10000 Cedar Avenue, Cleveland, OH 44106, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Feinstein</LastName><ForeName>Timothy N</ForeName><Initials>TN</Initials><AffiliationInfo><Affiliation>Confocal Microscopy and Quantitative Imaging Core Facility, Van Andel Research Institute, 333 Bostwick Ave, N.E., Grand Rapids, MI 49503, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Steiner</LastName><ForeName>Jennifer A</ForeName><Initials>JA</Initials><AffiliationInfo><Affiliation>Laboratory of Translational Parkinson's Disease Research, Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave, N.E., Grand Rapids, MI 49503, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Escobar Galvis</LastName><ForeName>Martha L</ForeName><Initials>ML</Initials><AffiliationInfo><Affiliation>Laboratory of Translational Parkinson's Disease Research, Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave, N.E., Grand Rapids, MI 49503, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Prochiantz</LastName><ForeName>Alain</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, Paris, France; Institut National de la Santé et de la Recherche Médicale U1050, Labex Memolife, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Brundin</LastName><ForeName>Patrik</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Neuronal Survival Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC B11, 221 84 Lund, Sweden; Laboratory of Translational Parkinson's Disease Research, Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave, N.E., Grand Rapids, MI 49503, USA. Electronic address: Patrik.Brundin@vai.org.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>339379</GrantID><Agency>European Research Council</Agency><Country>International</Country></Grant><Grant><GrantID>P50 NS058830</GrantID><Acronym>NS</Acronym><Agency>NINDS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>P50-NS058830</GrantID><Acronym>NS</Acronym><Agency>NINDS NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2014</Year><Month>10</Month><Day>02</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Neurobiol Dis</MedlineTA><NlmUniqueID>9500169</NlmUniqueID><ISSNLinking>0969-9961</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C080330">En1 protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D018398">Homeodomain Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>102-32-9</RegistryNumber><NameOfSubstance UI="D015102">3,4-Dihydroxyphenylacetic Acid</NameOfSubstance></Chemical><Chemical><RegistryNumber>147336-22-9</RegistryNumber><NameOfSubstance UI="D049452">Green Fluorescent Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 1.14.16.2</RegistryNumber><NameOfSubstance UI="D014446">Tyrosine 3-Monooxygenase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="D058570">TOR Serine-Threonine Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="C546843">mTOR protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>X77S6GMS36</RegistryNumber><NameOfSubstance UI="D006719">Homovanillic Acid</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D015102" MajorTopicYN="N">3,4-Dihydroxyphenylacetic Acid</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001343" MajorTopicYN="N">Autophagy</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003342" MajorTopicYN="N">Corpus Striatum</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName><QualifierName UI="Q000473" MajorTopicYN="Y">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004195" MajorTopicYN="N">Disease Models, Animal</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018450" MajorTopicYN="N">Disease Progression</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D059290" MajorTopicYN="N">Dopaminergic Neurons</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName><QualifierName UI="Q000648" MajorTopicYN="N">ultrastructure</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005786" MajorTopicYN="N">Gene Expression Regulation</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D049452" MajorTopicYN="N">Green Fluorescent Proteins</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018398" 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MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013378" MajorTopicYN="N">Substantia Nigra</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000473" MajorTopicYN="Y">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013997" MajorTopicYN="N">Time Factors</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014446" MajorTopicYN="N">Tyrosine 3-Monooxygenase</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Autophagy</Keyword><Keyword MajorTopicYN="N">CLARITY</Keyword><Keyword MajorTopicYN="N">Dopamine transporter</Keyword><Keyword MajorTopicYN="N">En1(+/−) mice</Keyword><Keyword MajorTopicYN="N">Impaired dopamine release</Keyword><Keyword MajorTopicYN="N">In vivo electrochemistry</Keyword><Keyword MajorTopicYN="N">LC3</Keyword><Keyword MajorTopicYN="N">Retrograde degeneration</Keyword><Keyword MajorTopicYN="N">TH–GFP</Keyword><Keyword MajorTopicYN="N">mTOR</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2014</Year><Month>06</Month><Day>11</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2014</Year><Month>08</Month><Day>28</Day></PubMedPubDate><PubMedPubDate 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