PHF-TAU IN NEURODEGENERATIVE DIESEASES OF GUAM

描述(申请人提供)：影响神经退行性疾病 西太平洋马里亚纳群岛上的查莫罗类似于阿尔茨海默氏症 疾病(AD)、帕金森病(PD)和肌萎缩侧索硬化症(ALS) 在其他地方，但肌萎缩侧索硬化症，帕金森病和痴呆症经常在查莫罗斯共同发生，而这 该综合征被称为关岛肌萎缩侧索硬化症/帕金森痴呆症复合体(ALS/PDC)。然而， 与其他人群的AD、PD和ALS不同，关岛ALS/PDC的特点是 主要由中枢神经中丰富的神经原纤维缠结(NFTs)引起 渐进性退化的中枢神经系统神经元。ALS/PDC NFT是 与经典AD患者没有区别，但约25%的ALS/PDC大脑 含有类AD老年斑(SP)的抗体和类PD路易小体 (Lbs)最近在更多的人中检测到了a-突触核蛋白(a-syn)抗体 ALS/PDC大脑比以前认识的更多，这表明ALS/PDC不是 “纯粹的”紧张症。但是，ALS/PDC和传统AD中的NFT都是 形成的成对螺旋细丝(PHF)的神经元内聚集体 由所有6种脑tau亚型组成的过度磷酸化tau(PHF-tau)，而 含有3或4个微管结合重复序列的tau亚型在 在其他牛顿病症中发现的缠结。最近，我们培育了转基因小鼠 过度表达3R tau，令人惊讶的是，他们开发出了类似ALS/PDC的 表型提供了NFT样tau的第一个实验证据 夹杂物在ALS/PDC中起机械作用。尽管如此，我们也 假设SP和LBS有助于ALS/PDC的进展，以及 氧化/硝化损伤在NFT的发展中起作用 反过来，在这种疾病中，SP和LB的形成机制也起着重要作用。 因此，这个项目的具体目标将检验大脑的假设 ALS/PDC的退化是由于NFTs、SPS和LBS的积累造成的 分别由tau、Ab和a-syn诱导燃烧和/或 聚集体和氧化/硝化应激在其中起着重要作用 在ALS/PDC中处理。

DESCRIPTION (provided by applicant): Neurodegenerative diseases that affect Chamorros in the Mariana Islands of the Western Pacific resemble Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS) elsewhere, but ALS, PD and dementia frequently co-occur in Chamorros, and this syndrome is known as Guam ALS/Parkinson dementia complex (ALS/PDC). However, unlike AD, PD and ALS in other populations, Guam ALS/PDC is characterized predominantly by abundant neurofibrillary tangles (NFTs) in central nervous system (CNS) neurons that progressively degenerate. ALS/PDC NFTs are indistinguishable from those in classic AD, but about 25% of ALS/PDC brains contain AD-like senile plaque (SP) deposits of Ab, and PD-like Lewy bodies (LBs) were detected recently with antibodies to a-synuclein (a-syn) in more ALS/PDC brains than previously recognized indicating that ALS/PDC is not a "pure" tauopathy. However, the NFTs in both ALS/PDC and classic AD are intraneuronal aggregates of paired helical filaments (PHFs) formed by hyperphosphorylated tau (PHF-tau) composed of all 6 brain tau isoforms, while tau isoforms containing 3 or 4 microtubule binding repeats predominate in the tangles found in other tauopathies. Recently, we generated transgenic mice overexpressing 3R tau and surprisingly they developed an ALS/PDC-Iike phenotype to provide the first experimental evidence that NFT-like tau inclusions play a mechanistic role in ALS/PDC. Nonetheless, we also hypothesize that SPs and LBs contribute to the progression of ALS/PDC, and that oxidative/nitrative damage plays a role in the development of NFT which in turn contributes to mechanisms of SP and LB formation in this disorder. Thus, the Specific Aims of this project will test the hypothesis that brain degeneration in ALS/PDC results from accumulations of NFTs, SPs and LBs formed by tau, Ab and a-syn, respectively, that are induced to fibrillize and/or aggregate and oxidative/nitrative stress plays an important role in this process in ALS/PDC.