A53T human α-synuclein overexpression in transgenic mice induces pervasive mitochondria macroautophagy defects preceding dopamine neuron degeneration
| Autor: | Susie Turkson, Xiaoxi Zhuang, Zhiguo Xie, Linan Chen |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Genetically modified mouse
Ubiquitin-Protein Ligases PINK1 Cell Count Mice Transgenic Biology Mitochondrion Parkin Transgenic Model chemistry.chemical_compound Mice Mitophagy Autophagy Animals Humans Alpha-synuclein General Neuroscience Dopaminergic Neurons Parkinson Disease Articles Corpus Striatum Cell biology Mitochondria Disease Models Animal chemistry Nerve Degeneration alpha-Synuclein Protein Kinases |
| Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience. 35(3) |
| ISSN: | 1529-2401 |
| Popis: | In vitroevidence suggests that the inefficient removal of damaged mitochondria by macroautophagy contributes to Parkinson's disease (PD). Using a tissue-specific gene amplification strategy, we generated a transgenic mouse line with human α-synuclein A53T overexpression specifically in dopamine (DA) neurons. Transgenic mice showed profound early-onset mitochondria abnormalities, characterized by macroautophagy marker-positive cytoplasmic inclusions containing mainly mitochondrial remnants, which preceded the degeneration of DA neurons. Genetic deletion of either parkin or PINK1 in these transgenic mice significantly worsened mitochondrial pathologies, including drastically enlarged inclusions and loss of total mitochondria contents. These data suggest that mitochondria are the main targets of α-synuclein and their defective autophagic clearance plays a significant role during pathogenesis. Moreover, endogenous PINK1 or parkin is indispensable for the proper autophagic removal of damaged mitochondria. Our data for the first time establish an essential link between mitochondria macroautophagy impairments and DA neuron degeneration in anin vivomodel based on known PD genetics. The model, its well-defined pathologies, and the demonstration of a main pathogenesis pathway in the present study have set the stage and direction of emphasis for future studies. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|