The Role of HSP60 in Alzheimer's Disease

HSP60 在阿尔茨海默病中的作用

• 批准号: 10712368
• 负责人: Dhyan Chandra
• 金额: $ 29.62万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712368
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid; Apoptotic; Biology; Brain; CRISPR/Cas technology; Cancer Patient; Cell Death; Chaperonin 60; Collaborations; Defect; Dementia; Deposition; Development; Disease; Disease Progression; Genes; Goals; Human; Impaired cognition; Knock-in Mouse; Malignant neoplasm of prostate; Mediating; Memory Loss; Memory impairment; Mitochondria; Mitochondrial Proteins; Molecular; Molecular Chaperones; Mus; Mutation; Neurodegenerative Disorders; Neurofibrillary Tangles; Phenotype; Play; Point Mutation; Positioning Attribute; Prognosis; Proteins; Research; Resources; Role; Senile Plaques; Signal Transduction; Testing; Wild Type Mouse; amyloid peptide; androgen deprivation therapy; brain tissue; cofactor; cognitive function; disease phenotype; disease prognosis; experience; extracellular; hyperphosphorylated tau; insight; misfolded protein; mitochondrial dysfunction; mouse model; novel; proteostasis; response; tau Proteins; tau aggregation; tau-1

Alzheimer’s disease (AD), the most common type of dementia, is characterized by progressive memory loss and impaired cognitive function. The development of these phenotypes associates with extracellular deposition of b- amyloid peptide, accumulation of hyperphosphorylated tau (phospho-tau) protein in brain, and alteration in mitochondrial biology and function. Whether and how mitochondria play role in the formation of b-amyloid plaques, which consist of b-amyloid peptide and neurofibrillary tangles (NFTs) containing phosphor-tau protein, are not clearly understood. Mitochondrial protein homeostasis (mitochondrial proteostasis) is mediated by mitochondrial unfolded protein response (UPRmt). UPRmt is regulated by chaperones such as heat shock protein 60 (HSP60). Oligomerization of HSP60 and association with its cofactor HSP10, maintain mitochondrial proteostasis via folding of naïve proteins and refolding of misfolded proteins. We have generated a unique mouse model by introducing a point mutation at position 3 (D3G) of the mature mitochondrial HSP60 protein (HSP60D3G knock-in mice) via CRISPR-Cas9 approach. HSP60D3G destabilizes the oligomerization of HSP60 leading to the accumulation of unfolded/misfolded proteins in mitochondria. Importantly, a point mutation at position 3 (D3G) of the mature mitochondrial HSP60 protein (HSP60D3G or D29G mutation in HSPD1 gene) also associates with neurodegenerative disorder. Therefore, the utilization of this unique mouse model will address a critical unmet need to characterize the levels and functional significance of b-amyloid and phospho-tau accumulation upon disrupting the mitochondrial proteostasis. Using HSP60D3G knock-in mouse model, we will study molecular insights of AD biology and functional significance of defects in mitochondrial proteostasis. We will dissect the underlying mechanism on whether/how destabilizing mitochondrial proteostasis leads to enhanced levels of b-amyloid and phospho-tau accumulation causing decline of cognitive function in HSP60D3G mouse. We will test our hypothesis that destabilization of mitochondrial proteostasis enhances the accumulation of b-amyloid and phospho-tau in brain causing AD phenotypes in HSP60D3G mice. Two Specific Aims are proposed to test this hypothesis. Aim 1. Determine the significance of defective HSP60 oligomerization on cellular signaling that regulates b- amyloid and phospho-tau in mouse brain. Aim 2. Functional characterization of defective HSP60 oligomerization on cognitive function in HSP60D3G mice. Impact: Androgen deprivation therapy (ADT) associates with increased risk of AD in prostate cancer (PCa) patients. HSP60 is highly upregulated and required for PCa development and progression. Therefore, understanding the impact of defective HSP60 oligomerization will provide deeper understanding on the causes and consequences of developing AD in PCa patients undergoing ADT therapy. The findings may provide the impact of mitochondrial proteostasis in AD biology and prognosis including in PCa patients as well as identify HSP60 as a novel target for the treatment and management of AD in humans.

阿尔茨海默病（AD）是最常见的痴呆类型，其特征在于进行性记忆丧失， 认知功能受损这些表型的发展与细胞外沉积的B- 淀粉样肽、脑中过度磷酸化的tau（磷酸化tau）蛋白的积累，以及 线粒体生物学和功能。线粒体是否以及如何在b-淀粉样斑块的形成中发挥作用， 由β-淀粉样肽和含磷酸化tau蛋白的神经纤维缠结（NFT）组成， 明白线粒体蛋白质稳态（mitochondrial proteostasis）是由未折叠的线粒体介导的。 蛋白质反应（UPRmt）。UPRmt受分子伴侣如热休克蛋白60（HSP 60）调节。低聚 HSP 60及其辅助因子HSP 10通过折叠天然蛋白质维持线粒体蛋白质稳定 和错误折叠蛋白质的重折叠。我们已经通过在小鼠基因组中引入一个点突变， 通过CRISPR-Cas9方法测定成熟线粒体HSP 60蛋白（HSP 60 D3 G敲入小鼠）的位置3（D3 G）。 HSP 60 D3 G使HSP 60的寡聚化不稳定，导致未折叠/错误折叠的蛋白质在细胞中积累。 线粒体重要的是，在成熟线粒体HSP 60蛋白的位置3（D3 G）处的点突变（HSP 60 D3 G或D3 G）可导致线粒体HSP 60蛋白的突变。 HSPD 1基因的D29 G突变也与神经退行性疾病有关。因此，利用这种独特的 小鼠模型将解决一个关键的未满足的需要，以表征b-淀粉样蛋白的水平和功能意义， 在破坏线粒体蛋白质稳态后磷酸-tau积累。采用HSP 60 D3 G基因敲入小鼠模型， 将研究AD生物学的分子见解和线粒体蛋白质稳态缺陷的功能意义。我们 将剖析潜在的机制是否/如何破坏线粒体蛋白质稳态导致增强 β-淀粉样蛋白和磷酸化tau蛋白积累水平导致HSP 60 D3 G小鼠认知功能下降。我们将 验证我们假设线粒体蛋白质稳定的不稳定性增强了b-淀粉样蛋白的积累 和脑中的磷酸化tau蛋白导致HSP 60 D3 G小鼠的AD表型。提出了两个具体目标来检验这一点 假说. 目标1.确定缺陷性HSP 60寡聚化对调节B- 淀粉样蛋白和磷酸化tau蛋白。目标二。HSP 60寡聚化缺陷的功能表征 HSP 60 D3 G小鼠的认知功能。 影响：雄激素剥夺治疗（ADT）与前列腺癌（PCa）患者AD风险增加相关。 HSP 60是高度上调的，并且是PCa发展和进展所必需的。因此，了解影响 HSP 60寡聚化缺陷的研究将有助于更深入地了解HSP 60寡聚化缺陷的原因和后果。 接受ADT治疗的PCa患者中的AD。这一发现可能提供了线粒体蛋白质稳态在 AD生物学和预后，包括PCa患者，以及确定HSP 60作为治疗的新靶点， 人类AD的管理。