Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington's disease.
Huntington's disease (HD) is a fatal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion leading to an elongated polyglutamine stretch in huntingtin. Mutant huntingtin (mHTT) is ubiquitously expressed in all cells but elicits selective cortical and striatal neurodegeneration in HD. The mechanistic basis for such selective neuronal vulnerability remains unclear. A necessary step toward resolving this enigma is to define the cell types in which mHTT expression is causally linked to the disease pathogenesis. Using a conditional transgenic mouse model of HD, in which the mice express full-length human mHTT from a bacterial artificial chromosome transgene (BACHD), we genetically reduced mHTT expression in neuronal populations in the striatum, cortex or both. We show that reduction of cortical mHTT expression in BACHD mice partially improves motor and psychiatric-like behavioral deficits but does not improve neurodegeneration, whereas reduction of mHTT expression in both neuronal populations consistently ameliorates all behavioral deficits and selective brain atrophy in this HD model. Furthermore, whereas reduction of mHTT expression in cortical or striatal neurons partially ameliorates corticostriatal synaptic deficits, further restoration of striatal synaptic function can be achieved by reduction of mHTT expression in both neuronal cell types. Our study demonstrates distinct but interacting roles of cortical and striatal mHTT in HD pathogenesis and suggests that optimal HD therapeutics may require targeting mHTT in both cortical and striatal neurons.
1] Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, USA. [2] Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, California, USA. [3].
Nan
N
Wang
1] Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, USA. [2] Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, California, USA. [3] [4].
Michelle
M
Gray
1] Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, USA. [2] Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
Xiao-Hong
XH
Lu
1] Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, USA. [2] Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
Jeffrey P
JP
Cantle
1] Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, California, USA. [2] Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
Sandra M
SM
Holley
1] Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, USA. [2] Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, California, USA. [3] Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California, USA.
Erin
E
Greiner
1] Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, USA. [2] Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
Xiaofeng
X
Gu
1] Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, USA. [2] Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, California, USA. [3] Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California, USA.
Dyna
D
Shirasaki
1] Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, California, USA. [2] Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
Carlos
C
Cepeda
Department of Neurology, College of Medicine, University of Florida, Gainesville, Florida, USA.
Yuqing
Y
Li
1] Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [2].
Hongwei
H
Dong
1] Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, California, USA. [2] Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
Michael S
MS
Levine
1] Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California, USA. [2] Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, California, USA. [3] Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
X William
XW
Yang
D000818:Animals; D001526:Behavioral Symptoms / Q000235:genetics* / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051379:Mice; D009043:Motor Activity / Q000235:genetics; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins