期刊
JOURNAL OF PHYSIOLOGY-LONDON
卷 599, 期 9, 页码 2483-2498出版社
WILEY
DOI: 10.1113/JP277459
关键词
Tau; Phosphorylation; AMPA Receptors; Dendritic Spines; Postsynaptic Dysfunction; Alzheimer' s Disease
资金
- NIA NIH HHS [RF1 AG060766] Funding Source: Medline
- NIGMS NIH HHS [T32 GM008471] Funding Source: Medline
- NINDS NIH HHS [R21 NS096437, R21 NS084007, R01 NS079374] Funding Source: Medline
Mislocalization of Tau protein to dendritic spines and associated postsynaptic deficits are mediated through distinct phosphorylation sites. Phosphorylation at different domains of Tau protein leads to sequential processes resulting in synaptic dysfunction. Glycogen synthetase kinase 3 beta and cyclin-dependent kinase 5 play crucial roles in preventing Tau mislocalization to dendritic spines.
Key points Tau mislocalization to dendritic spines and associated postsynaptic deficits are mediated through different and non-overlapping phosphorylation sites. Tau mislocalization to dendritic spines depends upon the phosphorylation of either Ser396 or Ser404 in the C-terminus. Postsynaptic dysfunction instead depends upon the phosphorylation of at least one of five residues in the proline-rich region of tau. The blockade of both glycogen synthetase kinase 3 beta and cyclin-dependent kinase 5 is required to prevent P301L-induced tau mislocalization to dendritic spines, supporting redundant pathways that control tau mislocalization to spines. Tau protein consists of an N-terminal projection domain, a microtubule-binding domain and a C-terminal domain. In neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia, the hyperphosphorylation of tau changes its shape, binding partners and resulting function. An early consequence of tau phosphorylation by proline-directed kinases is postsynaptic dysfunction associated with the mislocalization of tau to dendritic spines. The specific phosphorylation sites leading to these abnormalities have not been elucidated. Here, using imaging and electrophysiological techniques to study cultured rat hippocampal neurons, we show that postsynaptic dysfunction results from a sequential process involving differential phosphorylation in the N-terminal and C-terminal domains. First, tau mislocalizes to dendritic spines, in a manner that depends upon the phosphorylation of either Ser396 or Ser404 in the C-terminal domain. The blockade of both glycogen synthetase kinase 3 beta and cyclin-dependent kinase 5 prevents tau mislocalization to dendritic spines. Second, a reduction of functional AMPA receptors depends upon the phosphorylation of at least one of five residues (Ser202, Thr205, Thr212, Thr217 and Thr231) in the proline-rich region of the N-terminal domain. This is the first report of differential phosphorylation in distinct tau domains governing separate, but linked, steps leading to synaptic dysfunction.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据