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LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00005356naa a2200493 4500
001oai:lup.lub.lu.se:170882a7-75f4-4b28-aed2-ecaf742b28a3
003SwePub
008160401s2015 | |||||||||||000 ||eng|
0247 a https://lup.lub.lu.se/record/47382312 URI
0247 a https://doi.org/10.1016/j.nbd.2014.09.0122 DOI
040 a (SwePub)lu
041 a engb eng
042 9 SwePub
072 7a art2 swepub-publicationtype
072 7a ref2 swepub-contenttype
1001 a Nordström, Ulrikau Lund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine4 aut0 (Swepub:lu)med-uan
2451 0a Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease.
264 1b Elsevier BV,c 2015
338 a electronic2 rdacarrier
520 a 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.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Neurovetenskaper0 (SwePub)301052 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Neurosciences0 (SwePub)301052 hsv//eng
7001 a Beauvais, Geneviève4 aut
7001 a Ghosh, Anamitra4 aut
7001 a Pulikkaparambil Sasidharan, Baby Chakrapani4 aut
7001 a Lundblad, Martinu Lund University,Lunds universitet,Utvecklings- och regenerativ neurobiologi,Forskargrupper vid Lunds universitet,Developmental and Regenerative Neurobiology,Lund University Research Groups4 aut0 (Swepub:lu)mphy-mlu
7001 a Fuchs, Julia4 aut
7001 a Joshi, Rajiv L4 aut
7001 a Lipton, Jack W4 aut
7001 a Roholt, Andrew4 aut
7001 a Medicetty, Satish4 aut
7001 a Feinstein, Timothy N4 aut
7001 a Steiner, Jenniferu Lund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine4 aut0 (Swepub:lu)med-jfs
7001 a Escobar Galvis, Martha L4 aut
7001 a Prochiantz, Alain4 aut
7001 a Brundin, Patriku Lund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine4 aut0 (Swepub:lu)mphy-pbr
7102 a Institutionen för experimentell medicinsk vetenskapb Medicinska fakulteten4 org
7730 t Neurobiology of Diseased : Elsevier BVg 73, s. 70-82q 73<70-82x 0969-9961
8564 u https://portal.research.lu.se/files/1688430/5424430x primaryx freey FULLTEXT
8564 u http://www.ncbi.nlm.nih.gov/pubmed/25281317?dopt=Abstracty FULLTEXT
8564 u http://dx.doi.org/10.1016/j.nbd.2014.09.012y FULLTEXT
8564 u https://doi.org/10.1016/j.nbd.2014.09.012
8564 8u https://lup.lub.lu.se/record/4738231
8564 8u https://doi.org/10.1016/j.nbd.2014.09.012

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