BIOLOGY OF CHROMOSOME 17 LINKED DEMENTIA WITH TAUOPATHY

描述（申请人摘要）：申请人最近描述了 一个遗传性早老性痴呆的七代家系。 影响 家庭成员出现症状的平均年龄为48.8岁 （范围39-59）。 最初的临床特征包括不平衡， 记忆丧失和吞咽困难进一步导致认知能力下降，共济失调， 以及由明显的上上级凝视麻痹组成的锥体外系体征。 神经病理学研究表明，中枢神经系统的神经元损失 系统沿着与嗜银，tau免疫阳性包涵体的神经元， 和少突胶质细胞。 从黑猩猩大脑中分离出的扭曲细丝 受影响的家族成员由tau蛋白组成，直径不同， 阿尔茨海默病成对螺旋丝的周期性。这些 病变不伴有S-淀粉样蛋白沉积。 由于临床 和分子病理特征，该疾病具有 被称为家族性多系统tau蛋白病伴早老性痴呆 （MSTD）。 使用来自家庭成员的DNA进行有限的基因组筛选， 将该病定位于染色体17 q的3cM区域（THRA 1-D17 S791）。 目的 该建议的主要目的是（1）鉴定第一个 MSTD家族和最近发现的新家族，以及任何新的 （2）如果他们将成为可用的亲属;（2）描述病理学 两个MSTD家族和任何其他可能出现的表型，（3）阐明 负责神经系统发育的机制 表征疾病的病变;以及（4）分离负责的基因。 鉴于MSTD具有共同的分子病理学特征， 阿尔茨海默病、皮质基底节变性和 进行性核上性麻痹，确定MSTD的遗传基础， 是了解这些疾病分子发病机制的第一步， 神经退行性疾病 我们的研究代表了一个多学科的团队 研究遗传性退化性痴呆的方法， 这种方法在研究家族性疾病方面取得了宝贵的成功， 阿尔茨海默病和朊病毒病。 团队成员高度 在奋进领域有丰富经验的调查员

DESCRIPTION (Applicant's Abstract): The applicants have recently described a hereditary presenile dementia in a seven generation pedigree. Affected family members presented with symptoms at an average age of 48.8 years (range 39-59). The initial clinical features included disequilibrium, memory loss and dysphagia processing to further cognitive decline, dystaxia, and extrapyramidal signs consisting of marked superior gaze palsy. Neuropathologic studies have shown neuronal loss in the central nervous system along with argentophilic, tau-immunopositive inclusions in neurons, and oligodendroglia cells. Twisted filaments isolated from brains of affected family members were composed of tau and differed in diameter and periodicity from the paired helical filaments of Alzheimer's disease.These lesions were not accompanied by s-amyloid deposits. Because of the clinical and molecular pathological characteristics of this family, the disease has been termed familial multiple system tauopathy with presenile dementia (MSTD). A limited genomic screen using DNA from family members localized the disease to a 3 cM region (THRA1-D17S791) of chromosome 17q. The purpose of this proposal is to (1) identify the pathologic phenotype of the first MSTD family and of the new family recently identified, as well as of any new kindred if they will become available; (2) characterize the pathological phenotype of two MSTD families and any other that may arise, (3) elucidate the mechanisms responsible for the development of the neurofibrillary lesions that characterize the disease; and (4) isolate the gene responsible. In view of the fact that MSTD shares dome molecular pathological characteristics with Alzheimer disease, corticobasal degeneration, and progressive supranuclear palsy, determining the genetic basis of MSTD would be the first step in understanding the molecular pathogenesis of these neurodegenerative diseases. Our studies represent a multidisciplinary team approach directed to the study of hereditary degenerative dementias, an approach that has been successful preciously in the study of familial Alzheimer disease and prion diseases. The members of the team are highly experienced investigators in their field of endeavor.