|
Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis
Guohao Wang,Xudong Liu,Marta A. Gaertig,Shihua Li,and Xiao-Jiang Li
PNAS
Abstract
The Huntington’s disease (HD) protein, huntingtin (HTT), is essential for early development. Because suppressing the expression of mutant HTT is an important approach to treat the disease, we must first understand the normal function of Htt in adults versus younger animals. Using inducible Htt knockout mice, we found that Htt depletion does not lead to adult neurodegeneration or animal death at >4 mo of age, which was also verified by selectively depleting Htt in neurons. On the other hand, young Htt KO mice die at 2 mo of age of acute pancreatitis due to the degeneration of pancreatic acinar cells. Importantly, Htt interacts with the trypsin inhibitor, serine protease inhibitor Kazal-type 3 (Spink3), to inhibit activation of digestive enzymes in acinar cells in young mice, and transgenic HTT can rescue the early death of Htt KO mice. These findings point out age- and cell type-dependent vital functions of Htt and the safety of knocking down neuronal Htt expression in adult brains as a treatment.
|
论文编号: |
DOI:10.1073/pnas.1524575113 |
论文题目: |
Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis |
英文论文题目: |
Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis |
第一作者: |
Guohao Wang,Xudong Liu,Marta A. Gaertig,Shihua Li,and Xiao-Jiang Li |
英文第一作者: |
Guohao Wang,Xudong Liu,Marta A. Gaertig,Shihua Li,and Xiao-Jiang Li |
联系作者: |
|
英文联系作者: |
|
外单位作者单位: |
|
英文外单位作者单位: |
|
发表年度: |
2016-03-08 |
卷: |
|
期: |
|
页码: |
|
摘要: |
The Huntington’s disease (HD) protein, huntingtin (HTT), is essential for early development. Because suppressing the expression of mutant HTT is an important approach to treat the disease, we must first understand the normal function of Htt in adults versus younger animals. Using inducible Htt knockout mice, we found that Htt depletion does not lead to adult neurodegeneration or animal death at >4 mo of age, which was also verified by selectively depleting Htt in neurons. On the other hand, young Htt KO mice die at 2 mo of age of acute pancreatitis due to the degeneration of pancreatic acinar cells. Importantly, Htt interacts with the trypsin inhibitor, serine protease inhibitor Kazal-type 3 (Spink3), to inhibit activation of digestive enzymes in acinar cells in young mice, and transgenic HTT can rescue the early death of Htt KO mice. These findings point out age- and cell type-dependent vital functions of Htt and the safety of knocking down neuronal Htt expression in adult brains as a treatment. |
英文摘要: |
The Huntington’s disease (HD) protein, huntingtin (HTT), is essential for early development. Because suppressing the expression of mutant HTT is an important approach to treat the disease, we must first understand the normal function of Htt in adults versus younger animals. Using inducible Htt knockout mice, we found that Htt depletion does not lead to adult neurodegeneration or animal death at >4 mo of age, which was also verified by selectively depleting Htt in neurons. On the other hand, young Htt KO mice die at 2 mo of age of acute pancreatitis due to the degeneration of pancreatic acinar cells. Importantly, Htt interacts with the trypsin inhibitor, serine protease inhibitor Kazal-type 3 (Spink3), to inhibit activation of digestive enzymes in acinar cells in young mice, and transgenic HTT can rescue the early death of Htt KO mice. These findings point out age- and cell type-dependent vital functions of Htt and the safety of knocking down neuronal Htt expression in adult brains as a treatment. |
刊物名称: |
PNAS |
英文刊物名称: |
PNAS |
论文全文: |
|
英文论文全文: |
|
全文链接: |
|
其它备注: |
Guohao Wang,Xudong Liu,Marta A. Gaertig,Shihua Li,and Xiao-Jiang Li. Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis. PNAS. DOI:10.1073/pnas.1524575113 |
英文其它备注: |
|
学科: |
|
英文学科: |
|
影响因子: |
|
第一作者所在部门: |
|
英文第一作者所在部门: |
|
论文出处: |
|
英文论文出处: |
|
论文类别: |
|
英文论文类别: |
|
参与作者: |
|
英文参与作者: |
|
|