PHF-TAU IN NEURODEGENERATIVE DIESEASES OF GUAM

描述（由申请人提供）：影响神经退行性疾病 西太平洋马里亚纳群岛的查莫罗人类似于阿尔茨海默氏症 帕金森病（PD）和肌萎缩侧索硬化症（ALS） 在其他地方，但ALS，PD和痴呆症经常在查莫罗人中同时发生， 关岛ALS/帕金森痴呆综合征（ALS/PDC）然而，在这方面， 与其他人群中的AD、PD和ALS不同，关岛ALS/PDC的特征是 主要由中枢神经系统中丰富的神经元缠结（NFT）引起 逐渐退化的系统（中枢神经系统）神经元。ALS/PDC NFT是 与经典AD中的那些没有区别，但是大约25%的ALS/PDC大脑 含有AD样老年斑（SP）Ab沉积物和PD样路易体 (LBs)最近在更多的人中检测到α-突触核蛋白（α-syn）抗体。 ALS/PDC的大脑比以前认识到的，这表明ALS/PDC不是一个 “纯”tau蛋白病。然而，ALS/PDC和经典AD中的NFT均 成对螺旋丝（PHF）的神经元内聚集体， 过度磷酸化的tau（PHF-tau）由所有6种脑tau亚型组成，而 含有3或4个微管结合重复的tau亚型在细胞中占主导地位 其他tau蛋白病中发现的缠结。最近，我们培育了转基因小鼠， 令人惊讶的是，他们开发了一种类似ALS/PDC的 表型提供了第一个实验证据，NFT样tau蛋白 夹杂物在ALS/PDC中起机械作用。尽管如此，我们也 假设SP和LB有助于ALS/PDC的进展， 氧化/硝化损伤在NFT的发展中起作用， 反过来又有助于这种疾病中SP和LB形成的机制。 因此，该项目的具体目标将测试大脑 ALS/PDC的退化是由形成的NFT、SP和LB的积累引起的 分别由tau、Ab和a-syn诱导， 聚集体和氧化/硝化应激在其中起重要作用 在ALS/PDC中的过程。

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.