PTEN, Cell Cycle and Neurofibrillary Degeneration

PTEN，细胞周期和神经原纤维变性

• 批准号: 8240479
• 负责人: Francesca-Fang Liao
• 金额: $ 28.87万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240479
• 关键词: 1-Phosphatidylinositol 3-Kinase; Accounting; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Appearance; Autopsy; Biological; Brain; Brain region; Cancer Etiology; Cell Cycle; Cell Cycle Regulation; Cell Death; Cell model; Cells; Cessation of life; Chronic; Clinical; Complement; Cyclin D1; Cytoplasmic Protein; Deposition; Development; Disease; Distress; Down-Regulation; Ectopic Expression; Effectiveness; Event; Exposure to; Future; Gene Delivery; Gene Expression; Gene Transfer; Germ Cells; Glutamates; Goals; Hippocampus (Brain); Human; Immunotherapy; Injection of therapeutic agent; Lipids; Mediating; Mitotic; Modeling; Molecular; Mus; N-Methylaspartate; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nuclear; Outcome Study; PTEN gene; Pathogenesis; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Prevention strategy; Principal Investigator; Process; Protein phosphatase; Reporting; Risk; Role; Senile Plaques; Signal Pathway; Signal Transduction; Small Interfering RNA; Specimen; Staging; Stress; Subfamily lentivirinae; Supplementation; Symptoms; System; Tauopathies; Testing; Therapeutic; Therapeutic Agents; Transgenic Mice; Transgenic Model; Tumor Suppressor Proteins; Work; abstracting; base; compare effectiveness; design; disease diagnosis; entorhinal cortex; gene therapy; improved; inhibitor/antagonist; kainate; mild neurocognitive impairment; mouse model; neuron loss; novel therapeutic intervention; novel therapeutics; prevent; programs; response; secretase; synaptic function; treatment strategy

Abstract In Alzheimer's disease (AD), the appearance of neurofibrillary tangles (NFTs) and massive neuronal death/loss in selected brain regions are widely accepted as the two major hallmarks. Although NFTs are coincident with cell death in several neurodegenerative diseases, known as tauopathies, and most notably in AD, the molecular mechanisms leading to this chronic loss of neuronal cells is still not understood. Ectopic expression of cell cycle markers, indicating aberrant cell cycle reentry, has been reported to be associated with neuronal death in both transgenic (Tg) mouse and human AD brains. Hence, a ¿cell cycle hypothesis¿ was proposed that these cell cycle events (CCEs) play a central causative role and represent the first step in the development of this devastating disease. This model complements the ¿amyloid hypothesis.¿. However, direct proof of a causative role for CCEs is lacking and the upstream regulatory factors are unknown. We now identify the tumor suppressor PTEN as an upstream factor governing the CCEs in post-mitotic neurons based on our finding that nuclear PTEN regulates the neuronal cell cycle. Moreover, this cell cycle regulatory function is spatially separated from the classic role of PTEN in the PI3 kinase-Akt signaling pathway, which is mediated primarily by the cytoplasmic protein. Loss of PTEN (nuclear PTEN, in particular) was found in AD-relevant regions in both Tg mice and human diseased brains which correlated with CCEs. We speculate that this loss of nuclear PTEN is one of the early causative factors in CCEs and that lentivirus-delivered nuclear PTEN gene transfer may not only block CCEs but also halt subsequent neurodegeneration. Studies proposed herein will aim to validate the cell cycle hypothesis and examine nuclear PTEN in an AD mouse model. Four specific aims are proposed to achieve this goal: 1) Quantitative analysis of PTEN/pAkt profiles and CCEs in mild cognitive impairment (MCI) and AD brains 2) Profile the pAkt level and its kinase activity in the triple Tg mouse model of AD 3) To investigate an early possible cause for CCEs in the triple Tg model and 4) To assess the effectiveness of lentivirus-delivered nuclear PTEN in treating CCEs and neurodegeneration in the triple Tg mouse model. This work will be instrumental to the future design of new therapeutic interventions, not only aiming at symptom-relief but also at disease-modifying mechanisms. Besides therapy, this study may also help validate CCEs as an early marker for disease diagnosis Project Narrative We aim to validate two new concepts that aberrant cell cycle events are one of the important disease mechanisms in AD and that lentivirus-delivered nuclear PTEN gene transfer in CNS can prevent these events in an AD mouse model. This work should have great impact on exploring a new class of cell cycle inhibitors in future preventive and treatment strategies of AD once these concepts are validated.

摘要

项目成果

Soluble beta-amyloid peptides, but not insoluble fibrils, have specific effect on neuronal microRNA expression.

• DOI: 10.1371/journal.pone.0090770
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Li JJ;Dolios G;Wang R;Liao FF
• 通讯作者: Liao FF

Anti-oxidant polydatin (piceid) protects against substantia nigral motor degeneration in multiple rodent models of Parkinson's disease.

• DOI: 10.1186/1750-1326-10-4
• 发表时间: 2015-03-02
• 期刊: Molecular neurodegeneration
• 影响因子: 15.1
• 作者: Chen Y;Zhang DQ;Liao Z;Wang B;Gong S;Wang C;Zhang MZ;Wang GH;Cai H;Liao FF;Xu JP
• 通讯作者: Xu JP