BIOLOGY OF CHROMOSOME 17 LINKED DEMENTIA WITH TAUOPATHY

描述(申请人摘要)：申请人最近描述 遗传性老年期前痴呆一家系七代。受影响 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平衡不平衡， 记忆丧失和吞咽困难导致进一步的认知能力下降， 锥体外系体征表现为明显的上凝视麻痹。 神经病理学研究表明，中枢神经中的神经元丢失 系统以及神经元中嗜银的tau免疫阳性包涵体， 和少突胶质细胞。从小鼠脑中分离出扭曲的细丝 受影响的家庭成员由tau组成，直径不同， 阿尔茨海默病患者成对螺旋细丝的周期性 病变未伴有S淀粉样物沉积。因为临床上 该家系的分子病理特征，本病有 被称为家族性多系统共济失调伴老年前期痴呆 (MSTD)。一种使用本地化家庭成员DNA的有限基因组筛选 本病位于染色体17q的3 cM区域(THRA1-D17S791)。目的 这一建议的目的是(1)鉴定第一个 MSTD家族和最近发现的新家族，以及任何新的 如果它们将变得可用，则为亲属；(2)描述病理的 两个MSTD家系的表型和可能出现的任何其他表型，(3)阐明 神经原纤维发育的机制 疾病特征的损伤；以及(4)分离负责的基因。 鉴于MSTD分享穹顶分子病理的事实 阿尔茨海默病、皮质基底膜变性和 进行性核上性麻痹，确定MSTD的遗传基础将 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 遗传性退行性痴呆的研究方向和方法 在家族性精神障碍研究中取得重大成功的方法 阿尔茨海默病和普恩病毒疾病。这个团队的成员们都高度重视 在他们的努力领域中有经验的调查人员。

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.