Huntington's disease (HD) represents an age-dependent neurodegenerative disease family including Alzheimer's (AD) and Parkinson's (PD) diseases. These diseases are characterized by selective neurodegeneration that is caused by misfolded proteins in an age-dependent manner. In HD, the disease protein huntingtin (htt) carries an expanded polyglutamine repeat, accumulates in the brain, forms aggregates as patients become old, and causes progressive neurological symptoms. Given the known genetic mutation in HD and its well-characterized neuropathology, HD makes an ideal model for investigating how selective neuropathology occurs in an age-dependent manner. Most previous studies focused on the effect of mutant htt on neuronal cells and revealed that N-terminal fragments of mutant htt are misfolded and cause cell-autonomous and non-cell-autonomous pathological events in a variety of animal models. In the brain, the majority of cells are non-neuronal cells that provide essential support to the survival and function of neuronal cells. These non-neuronal cells mainly consist of three types of glial cells: astrocytes, microglial cells and oligodendrocytes. It is known that oligodendrocytes produce myelin proteins for myelination of axons, and astrocytes can release neurotrophins to support neuronal survival and function. However, whether mutant htt in glial cells affects these important functions remains to be investigated. We have established transgenic mouse models that express mutant htt specifically in astrocytes (GFAP-160Q) or oligodendrocytes (PLP-150Q). Both HD mouse models develop age-dependent neurological phenotypes, suggesting that mutant htt in glial cells affects glial function during aging and critically contribute to the age-dependent clinical phenotypes. We also found that in our GFAP-160Q HD transgenic mice, mutant htt can reduce BDNF release from astrocytes and cause demyelination or neuronal death reminiscent the pathological events in previous HD mouse models and human HD patient's brains. In this application, we propose three aims to investigate how expression of mutant htt in glial cells causes neuronal dysfunction and neurological phenotypes in HD transgenic mice.
Aim 1 is to examine the effect of mutant htt on secretion of neurotrophic factors from glial cells.
Aim 2 is to explore how mutant htt in glial cells causes age-dependent neurological phenotypes and neuropathology.
Aim 3 is to investigate the protective effects of reducing htt in glial cells or improving glial function in HD mouse brains. These studies will help understand the mechanisms for age-dependent neuropathology in HD and the contribution of glial htt to HD pathology. Because glial cells are a desirable transplant population for therapy, the findings from our study may also provide a new therapeutic target for treating HD.

Public Health Relevance

We generated Huntington disease transgenic mice, which express mutant huntingtin in glial cells, and will use these mice to investigate how mutant huntingtin in glial cells causes age-dependent neuropathology and neurological phenotypes in mice. We will also explore the protective effect of knocking down mutant huntingtin specifically in glial cell on the HD neuropathology and phenotypes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS095181-04
Application #
9532956
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Miller, Daniel L
Project Start
2015-09-15
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Guo, Jifeng; Cui, Yiting; Liu, Qiong et al. (2018) Piperine ameliorates SCA17 neuropathology by reducing ER stress. Mol Neurodegener 13:4
Yan, Sen; Tu, Zhuchi; Liu, Zhaoming et al. (2018) A Huntingtin Knockin Pig Model Recapitulates Features of Selective Neurodegeneration in Huntington's Disease. Cell 173:989-1002.e13
Tu, Zhuchi; Yang, Weili; Yan, Sen et al. (2017) Promoting Cas9 degradation reduces mosaic mutations in non-human primate embryos. Sci Rep 7:42081
Yang, Su; Yang, Huiming; Chang, Renbao et al. (2017) MANF regulates hypothalamic control of food intake and body weight. Nat Commun 8:579
Hong, Yan; Zhao, Ting; Li, Xiao-Jiang et al. (2017) Mutant Huntingtin Inhibits ?B-Crystallin Expression and Impairs Exosome Secretion from Astrocytes. J Neurosci 37:9550-9563
Li, Xiao-Jiang; Tu, Zhuchi; Yang, Weili et al. (2017) CRISPR: Established Editor of Human Embryos? Cell Stem Cell 21:295-296
Yang, Su; Chang, Renbao; Yang, Huiming et al. (2017) CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington's disease. J Clin Invest 127:2719-2724
Cui, Yiting; Yang, Su; Li, Xiao-Jiang et al. (2017) Genetically modified rodent models of SCA17. J Neurosci Res 95:1540-1547
Xiang, Jianxing; Yang, Su; Xin, Ning et al. (2017) DYRK1A regulates Hap1-Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome. Proc Natl Acad Sci U S A 114:E1224-E1233
Yang, Yang; Yang, Su; Guo, Jifeng et al. (2017) Synergistic Toxicity of Polyglutamine-Expanded TATA-Binding Protein in Glia and Neuronal Cells: Therapeutic Implications for Spinocerebellar Ataxia 17. J Neurosci 37:9101-9115

Showing the most recent 10 out of 27 publications