Investigating Pathogenic Mechanisms of Frontotemporal Dementia Caused by Mutations in CHMP2B and TBK1

摘要 额颞叶痴呆（FTD）是一种进行性神经退行性疾病， 前额叶和/或颞叶FTD是第二种最常见的痴呆症， 65岁在过去的十年中，已经鉴定了许多导致FTD的基因，包括CHMP 2B， GRN、C9 ORF 72和TBK 1。其中一些基因也与运动神经元疾病有关 肌萎缩侧索硬化症（ALS），为深入研究致病机制铺平了道路。 在这两种疾病中。为了揭示不同形式FTD的共同致病机制， 研究常见和罕见的基因突变至关重要。为此，在本申请中，我们 将重点关注FTD引起的CHMP 2B和TBK 1突变对内体功能的影响， 溶酶体和自噬途径，两个密切相关的细胞途径降解跨膜 和细胞内货物。我们将利用不同实验系统的优势，包括果蝇 FTD的果蝇、小鼠模型和从CRISPR工程诱导分化的皮质神经元 多能干细胞（iPSC）。这种多学科的方法将大大提高我们对 FTD的致病机制，并揭示治疗干预的新靶点。

ABSTRACT Frontotemporal dementia (FTD) is a progressive neurodegenerative disease associated with focal atrophy of the prefrontal and/or temporal lobes. FTD is the second most common form of dementia among people under the age of 65. Many FTD-causing genes have been identified during the last decade, including CHMP2B, GRN, C9ORF72, and TBK1. Some of these genes are also implicated in the motor neuron disease amyotrophic lateral sclerosis (ALS), paving the way for in-depth mechanistic investigation of pathogenic processes in both disorders. In order to reveal common pathogenic mechanisms in different forms of FTD, it is critically important to investigate both common and rare genetic mutations. To this end, in this application, we will focus on the effects of FTD-causing mutations in CHMP2B and TBK1 on the functions of the endosomal- lysosomal and autophagy pathways, two closely linked cellular pathways for degradation of transmembrane and intracellular cargos. We will take advantage of strengths of different experimental systems including fruitfly Drosophila, mouse models of FTD and cortical neurons differentiated from CRISPR-engineered induced pluripotent stem cells (iPSCs). This multidisciplinary approach will greatly enhance our understanding of pathogenic mechanisms of FTD and reveal novel targets for therapeutic intervention.