دورية أكاديمية
أعرض في EDS

E46K mutant α-synuclein is more degradation resistant and exhibits greater toxic effects than wild-type α-synuclein in Drosophila models of Parkinson's disease.

التفاصيل البيبلوغرافية
العنوان: E46K mutant α-synuclein is more degradation resistant and exhibits greater toxic effects than wild-type α-synuclein in Drosophila models of Parkinson's disease.
المؤلفون: Sakai R; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.; Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan., Suzuki M; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.; Diabetic Neuropathy Project, Department of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo, Japan., Ueyama M; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan., Takeuchi T; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan., Minakawa EN; Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan., Hayakawa H; Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan., Baba K; Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan., Mochizuki H; Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan., Nagai Y; Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.; Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
المصدر: PloS one [PLoS One] 2019 Jun 26; Vol. 14 (6), pp. e0218261. Date of Electronic Publication: 2019 Jun 26 (Print Publication: 2019).
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
أسماء مطبوعة: Original Publication: San Francisco, CA : Public Library of Science
مواضيع طبية MeSH: Mutation, Missense*, Parkinson Disease/*metabolism , alpha-Synuclein/*metabolism, Animals ; Animals, Genetically Modified ; Disease Models, Animal ; Drosophila ; Humans ; Parkinson Disease/pathology ; Proteolysis ; alpha-Synuclein/genetics
مستخلص: Parkinson's disease (PD) is one of the most common neurodegenerative diseases, which is characterized by progressive motor dysfunction as well as non-motor symptoms. Pathological and genetic studies have demonstrated that α-synuclein (αSyn) plays key roles in the pathogenesis of PD. Although several missense mutations in the αSyn gene have been identified as causes of familial PD, the mechanisms underlying the variance in the clinical phenotypes of familial PD caused by different mutations remain elusive. Here, we established novel Drosophila models expressing either wild-type (WT) αSyn or one of five αSyn mutants (A30P, E46K, H50Q, G51D, and A53T) using site-specific transgenesis, which express transgenes at equivalent levels. Expression of either WT or mutant αSyn in the compound eyes by the GMR-GAL4 driver caused mild rough eye phenotypes with no obvious difference among the mutants. Upon pan-neuronal expression by the nSyb-GAL4 driver, these αSyn-expressing flies showed a progressive decline in locomotor function. Notably, we found that E46K, H50Q, G51D, and A53T αSyn-expressing flies showed earlier onset of locomotor dysfunction than WT αSyn-expressing flies, suggesting their enhanced toxic effects. Whereas mRNA levels of WT and mutant αSyn were almost equivalent, we found that protein expression levels of E46K αSyn were higher than those of WT αSyn. In vivo chase experiments using the drug-inducible GMR-GeneSwitch driver demonstrated that degradation of E46K αSyn protein was significantly slower than WT αSyn protein, indicating that the E46K αSyn mutant gains resistance to degradation in vivo. We therefore conclude that our novel site-specific transgenic fly models expressing either WT or mutant αSyn are useful to explore the mechanisms by which different αSyn mutants gain toxic functions in vivo.
Competing Interests: The authors have declared that no competing interests exist.
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المشرفين على المادة: 0 (alpha-Synuclein)
تواريخ الأحداث: Date Created: 20190627 Date Completed: 20200226 Latest Revision: 20200309
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC6594597
DOI: 10.1371/journal.pone.0218261
PMID: 31242217
قاعدة البيانات: MEDLINE
الوصف
تدمد:1932-6203
DOI:10.1371/journal.pone.0218261