دورية أكاديمية
Accumulation of mitochondrial DNA deletions within dopaminergic neurons triggers neuroprotective mechanisms.
| العنوان: | Accumulation of mitochondrial DNA deletions within dopaminergic neurons triggers neuroprotective mechanisms. |
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| المؤلفون: | Perier C; Vall d'Hebron Research Institute and Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain. cperier@ir.vhebron.net, Bender A, García-Arumí E, Melià MJ, Bové J, Laub C, Klopstock T, Elstner M, Mounsey RB, Teismann P, Prolla T, Andreu AL, Vila M |
| المصدر: | Brain : a journal of neurology [Brain] 2013 Aug; Vol. 136 (Pt 8), pp. 2369-78. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: England NLM ID: 0372537 Publication Model: Print Cited Medium: Internet ISSN: 1460-2156 (Electronic) Linking ISSN: 00068950 NLM ISO Abbreviation: Brain Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Oxford : Oxford University Press Original Publication: London. |
| مواضيع طبية MeSH: | Corpus Striatum/*metabolism , DNA, Mitochondrial/*genetics , Dopaminergic Neurons/*metabolism , Parkinson Disease/*genetics , Substantia Nigra/*metabolism, Animals ; Cell Death/genetics ; Corpus Striatum/pathology ; DNA Polymerase gamma ; DNA, Mitochondrial/metabolism ; DNA-Directed DNA Polymerase/genetics ; DNA-Directed DNA Polymerase/metabolism ; Dopaminergic Neurons/pathology ; Mice ; Mice, Transgenic ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondria/pathology ; Parkinson Disease/metabolism ; Parkinson Disease/pathology ; Substantia Nigra/pathology |
| مستخلص: | Acquired alterations in mitochondrial DNA are believed to play a pathogenic role in Parkinson's disease. In particular, accumulation of mitochondrial DNA deletions has been observed in substantia nigra pars compacta dopaminergic neurons from patients with Parkinson's disease and aged individuals. Also, mutations in mitochondrial DNA polymerase gamma result in multiple mitochondrial DNA deletions that can be associated with levodopa-responsive parkinsonism and severe substantia nigra pars compacta dopaminergic neurodegeneration. However, whether mitochondrial DNA deletions play a causative role in the demise of dopaminergic neurons remains unknown. Here we assessed the potential pathogenic effects of mitochondrial DNA deletions on the dopaminergic nigrostriatal system by using mutant mice possessing a proofreading-deficient form of mitochondrial DNA polymerase gamma (POLGD257A), which results in a time-dependent accumulation of mitochondrial DNA deletions in several tissues, including the brain. In these animals, we assessed the occurrence of mitochondrial DNA deletions within individual substantia nigra pars compacta dopaminergic neurons, by laser capture microdissection and quantitative real-time polymerase chain reaction, and determined the potential deleterious effects of such mitochondrial DNA alterations on mitochondrial function and dopaminergic neuronal integrity, by cytochrome c oxidase histochemistry and quantitative morphology. Nigral dopaminergic neurons from POLGD257A mice accumulate mitochondrial DNA deletions to a similar extent (∼40-60%) as patients with Parkinson's disease and aged individuals. Despite such high levels of mitochondrial DNA deletions, the majority of substantia nigra pars compacta dopaminergic neurons from these animals did not exhibit mitochondrial dysfunction or degeneration. Only a few individual substantia nigra pars compacta neurons appeared as cytochrome c oxidase-negative, which exhibited higher levels of mitochondrial DNA deletions than cytochrome c oxidase-positive cells (60.38±3.92% versus 45.18±2.83%). Survival of dopaminergic neurons in POLGD257A mice was associated with increased mitochondrial DNA copy number, enhanced mitochondrial cristae network, improved mitochondrial respiration, decreased exacerbation of mitochondria-derived reactive oxygen species, greater striatal dopamine levels and resistance to parkinsonian mitochondrial neurotoxins. These results indicate that primary accumulation of mitochondrial DNA deletions within substantia nigra pars compacta dopaminergic neurons, at an extent similar to that observed in patients with Parkinson's disease, do not kill dopaminergic neurons but trigger neuroprotective compensatory mechanisms at a mitochondrial level that may account for the high pathogenic threshold of mitochondrial DNA deletions in these cells. |
| فهرسة مساهمة: | Keywords: Parkinson disease; mitochondria; mtDNA deletions; neurodegeneration |
| المشرفين على المادة: | 0 (DNA, Mitochondrial) EC 2.7.7.7 (DNA Polymerase gamma) EC 2.7.7.7 (DNA-Directed DNA Polymerase) EC 2.7.7.7 (Polg protein, mouse) |
| تواريخ الأحداث: | Date Created: 20130726 Date Completed: 20131030 Latest Revision: 20171116 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1093/brain/awt196 |
| PMID: | 23884809 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1460-2156 |
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| DOI: | 10.1093/brain/awt196 |