Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Genetics & Genomics Graduate Program, Baylor College of Medicine, Houston, United States
Andrew Laitman
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Quantitative & Computational Biosciences, Baylor College of Medicine, Houston, United States; Department of Pediatrics, Baylor College of Medicine, Houston, United States
He Zhao
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States
Ryan Keyho
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States
Hyemin Kim
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States
Jennifer Wang
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States
Megan Mair
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Genetics & Genomics Graduate Program, Baylor College of Medicine, Houston, United States
Huilan Wang
State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
Lifang Li
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States
Alma Perez
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States
Maria de Haro
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States
Ying-Wooi Wan
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States
Genevera Allen
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Departments of Electrical & Computer Engineering, Statistics and Computer Science, Rice University, Houston, United States
Boxun Lu
State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
Ismael Al-Ramahi
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States
Zhandong Liu
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Quantitative & Computational Biosciences, Baylor College of Medicine, Houston, United States; Department of Pediatrics, Baylor College of Medicine, Houston, United States
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Genetics & Genomics Graduate Program, Baylor College of Medicine, Houston, United States; Quantitative & Computational Biosciences, Baylor College of Medicine, Houston, United States
Most research on neurodegenerative diseases has focused on neurons, yet glia help form and maintain the synapses whose loss is so prominent in these conditions. To investigate the contributions of glia to Huntington's disease (HD), we profiled the gene expression alterations of Drosophila expressing human mutant Huntingtin (mHTT) in either glia or neurons and compared these changes to what is observed in HD human and HD mice striata. A large portion of conserved genes are concordantly dysregulated across the three species; we tested these genes in a high-throughput behavioral assay and found that downregulation of genes involved in synapse assembly mitigated pathogenesis and behavioral deficits. To our surprise, reducing dNRXN3 function in glia was sufficient to improve the phenotype of flies expressing mHTT in neurons, suggesting that mHTT's toxic effects in glia ramify throughout the brain. This supports a model in which dampening synaptic function is protective because it attenuates the excitotoxicity that characterizes HD.
