Striatal Projection Neurons Require Huntingtin for Synaptic Connectivity and Survival
Caley J. Burrus,
Spencer U. McKinstry,
Namsoo Kim,
M. Ilcim Ozlu,
Aditya V. Santoki,
Francia Y. Fang,
Annie Ma,
Yonca B. Karadeniz,
Atesh K. Worthington,
Ioannis Dragatsis,
Scott Zeitlin,
Henry H. Yin,
Cagla Eroglu
Affiliations
Caley J. Burrus
Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
Spencer U. McKinstry
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
Namsoo Kim
Department of Psychology and Neuroscience, Trinity College of Arts and Sciences, Duke University, Durham, NC 27710, USA
M. Ilcim Ozlu
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
Aditya V. Santoki
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
Francia Y. Fang
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
Annie Ma
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
Yonca B. Karadeniz
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
Atesh K. Worthington
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
Ioannis Dragatsis
Department of Physiology, The University of Tennessee, Health Science Center, Memphis, TN 38163, USA
Scott Zeitlin
Department of Neuroscience, University of Virginia, School of Medicine, Charlottesville, VA 22908, USA
Henry H. Yin
Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Psychology and Neuroscience, Trinity College of Arts and Sciences, Duke University, Durham, NC 27710, USA; Duke Institute for Brain Sciences, Durham, NC 27710, USA
Cagla Eroglu
Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA; Duke Institute for Brain Sciences, Durham, NC 27710, USA; Regeneration Next Initiative, Duke University, Durham, NC 27710, USA; Corresponding author
Summary: Huntington’s disease (HD) is caused by an autosomal dominant polyglutamine expansion mutation of Huntingtin (HTT). HD patients suffer from progressive motor, cognitive, and psychiatric impairments, along with significant degeneration of the striatal projection neurons (SPNs) of the striatum. HD is widely accepted to be caused by a toxic gain-of-function of mutant HTT. However, whether loss of HTT function, because of dominant-negative effects of the mutant protein, plays a role in HD and whether HTT is required for SPN health and function are not known. Here, we delete Htt from specific subpopulations of SPNs using the Cre-Lox system and find that SPNs require HTT for motor regulation, synaptic development, cell health, and survival during aging. Our results suggest that loss of HTT function in SPNs could play a critical role in HD pathogenesis. : Burrus et al. show that striatal projection neurons require Huntingtin, the gene mutated in Huntington’s disease, for normal synaptic connectivity, regulated gene expression, and neuronal survival with aging. Loss of Huntingtin from striatal neurons recapitulates several features of Huntington’s disease pathology, an important consideration for therapies non-specifically targeting Huntingtin expression. Keywords: Huntington's Disease, basal ganglia, striatum, synaptic connectivity, neuronal survival
