TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation
| Autor: | Andus Hon-Kit Wong, Robert E. Drolet, Galya Vassileva, Cheryl A. Gretzula, Paige Cramer, Jyoti Disa, Marija Tadin-Strapps, David J. Stone, Bhavya Voleti, Sarah Jinn, Dawn Toolan |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Autophagosome Potassium Channels Primary Cell Culture Mitochondrion Biology Fibril Models Biological Pathogenesis Protein Aggregates 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Lysosome Autophagy medicine Animals Humans Ion channel Multidisciplinary Dopaminergic Neurons Autophagosomes Parkinson Disease Hydrogen-Ion Concentration Biological Sciences Mitochondria Rats Cell biology 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation alpha-Synuclein Transmembrane Protein 175 Glucosylceramidase Phosphorylation Lysosomes Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Proceedings of the National Academy of Sciences. 114:2389-2394 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1616332114 |
| Popis: | Parkinson disease (PD) is a neurodegenerative disorder pathologically characterized by nigrostriatal dopamine neuron loss and the postmortem presence of Lewy bodies, depositions of insoluble α-synuclein, and other proteins that likely contribute to cellular toxicity and death during the disease. Genetic and biochemical studies have implicated impaired lysosomal and mitochondrial function in the pathogenesis of PD. Transmembrane protein 175 (TMEM175), the lysosomal K+ channel, is centered under a major genome-wide association studies peak for PD, making it a potential candidate risk factor for the disease. To address the possibility that variation in TMEM175 could play a role in PD pathogenesis, TMEM175 function was investigated in a neuronal model system. Studies confirmed that TMEM175 deficiency results in unstable lysosomal pH, which led to decreased lysosomal catalytic activity, decreased glucocerebrosidase activity, impaired autophagosome clearance by the lysosome, and decreased mitochondrial respiration. Moreover, TMEM175 deficiency in rat primary neurons resulted in increased susceptibility to exogenous α-synuclein fibrils. Following α-synuclein fibril treatment, neurons deficient in TMEM175 were found to have increased phosphorylated and detergent-insoluble α-synuclein deposits. Taken together, data from these studies suggest that TMEM175 plays a direct and critical role in lysosomal and mitochondrial function and PD pathogenesis and highlight this ion channel as a potential therapeutic target for treating PD. |
| Databáze: | OpenAIRE |
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