Title: Astrocytic dynamin-like protein 1 regulates neuronal protection against excitotoxicity in Parkinson disease.
Authors: Hoekstra, Jake G; Cook, Travis J; Stewart, Tessandra; Mattison, Hayley; Dreisbach, Max T; Hoffer, Zachary S; Zhang, Jing
Published In Am J Pathol, (2015 Feb)
Abstract: Mitochondrial dynamics has recently become an area of piqued interest in neurodegenerative disorders, including Parkinson disease (PD); however, the contribution of astrocytes to these disorders remains unclear. Here, we show that the level of dynamin-like protein 1 (Dlp1; official name DNM1L), which promotes mitochondrial fission, is lower in astrocytes from the brains of PD patients, and that decreased astrocytic Dlp1 likely represents a relatively early event in PD pathogenesis. In support of this conclusion, we show that Dlp1 knockdown dramatically affects mitochondrial morphological characteristics and localization in astrocytes, impairs the ability of astrocytes to adequately protect neurons from the excitotoxic effects of glutamate, and increases intracellular Ca(2+) in response to extracellular glutamate, resulting from compromised intracellular Ca(2+) buffering. Taken together, our results suggest that astrocytic mitochondrial Dlp1 is a key protein in mitochondrial dynamics and decreased Dlp1 may interfere with neuron survival in PD by disrupting Ca(2+)-coupled glutamate uptake.
PubMed ID: 25482923
MeSH Terms: Astrocytes/metabolism; Astrocytes/pathology; Calcium Signaling*; Calcium/metabolism*; Cell Survival/genetics; Female; GTP Phosphohydrolases/genetics; GTP Phosphohydrolases/metabolism*; Gene Knockdown Techniques; Glutamic Acid/genetics; Glutamic Acid/metabolism; Humans; Male; Microtubule-Associated Proteins/genetics; Microtubule-Associated Proteins/metabolism*; Mitochondria/genetics; Mitochondria/metabolism*; Mitochondria/pathology; Mitochondrial Proteins/genetics; Mitochondrial Proteins/metabolism*; Neurons/metabolism*; Neurons/pathology; Parkinson Disease/genetics; Parkinson Disease/metabolism*; Parkinson Disease/pathology