title: Astrocytic dynamin-like protein 1 regulates neuronal protection against excitotoxicity in Parkinson disease.
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.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Jake G
authors.initials: JG
authors.lastname: Hoekstra
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington School of Public Health, Seattle, Washington.
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Cook
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Tessandra
authors.initials: T
authors.lastname: Stewart
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Hayley
authors.initials: H
authors.lastname: Mattison
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Max T
authors.initials: MT
authors.lastname: Dreisbach
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Hoffer
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington. Electronic address: zhangj@uw.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
mesh_terms: D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002470:Cell Survival / Q000235:genetics; D034281:Dynamins; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D018698:Glutamic Acid; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins; D002118:Calcium