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: Jake G Hoekstra, Travis J Cook, Tessandra Stewart, Hayley Mattison, Max T Dreisbach, Zachary S Hoffer, Jing Zhang
• Journal: The American journal of pathology (Am J Pathol) Vol. 185 Issue 2 Pg. 536-49 (Feb 2015) ISSN: 1525-2191 [Electronic] United States
• PMID: 25482923 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Microtubule-Associated Proteins
• Mitochondrial Proteins
• Glutamic Acid
• GTP Phosphohydrolases
• DNM1L protein, human
• Dynamins
• Calcium

Topics

• Astrocytes (metabolism, pathology)
• Calcium (metabolism)
• Calcium Signaling
• Cell Survival (genetics)
• Dynamins
• Female
• GTP Phosphohydrolases (genetics, metabolism)
• Gene Knockdown Techniques
• Glutamic Acid (genetics, metabolism)
• Humans
• Male
• Microtubule-Associated Proteins (genetics, metabolism)
• Mitochondria (genetics, metabolism, pathology)
• Mitochondrial Proteins (genetics, metabolism)
• Neurons (metabolism, pathology)
• Parkinson Disease (genetics, metabolism, pathology)