Cell-type-specific contributions to cortical dysfunction in frontotemporal dementia

细胞类型特异性对额颞叶痴呆皮质功能障碍的影响

基本信息

批准号：
10758410
负责人：
Rita Marie Cowell
金额：
$ 5.53万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10758410
关键词：
Cell type specific contributions cortical

项目摘要

PROJECT SUMMARY Frontotemporal dementia (FTD) is a debilitating, age-related neurodegenerative condition caused by frontotemporal lobar degeneration (FTLD), most often accompanied by the accumulation and/or dysfunction of the protein TDP-43 (FTLD-TDP). Aggregation of TDP-43, encoded by the TARDBP gene, occurs with or without concomitant mutations in TARDBP, suggesting that its accumulation represents a convergent mechanism underlying cortical vulnerability in FTD. The mechanisms underlying the detrimental effects of TDP-43 dysfunction are complex and likely involve both gain- and loss-of-function mechanisms, due to alterations in the intracellular compartmentalization and aggregation properties of TDP-43. Despite the availability of cell culture and mouse models of TDP-43 pathology, the precise mechanisms by which TARDBP mutations give rise to cortical dysfunction and cell loss in vivo are not clear. Recent imaging studies implicate a disruption in excitatory and inhibitory (E:I) balance in the cortex of patients with FTD, yet very little work has been done to explore the mechanisms by which this arises in vivo. Recent data generated using knockin and overexpression models of TDP-43 have revealed alterations in gene expression, function, and viability of cortical parvalbumin-expressing fast-spiking interneurons (PV-INs), cells which provide the main source of feed-forward GABAergic neurotransmission in the cortex and are critical for maintaining E:I balance. However, very little is known about the mechanisms underlying PV-IN vulnerability with Tardbp mutations in vivo and how PV-IN dysfunction contributes to pyramidal excitatory neuron function and loss. The experiments proposed in this application aim to identify the effects of TDP-43 mutation on PV-INs by assessing the PV-IN-specific transcriptional changes which occur during the progression of disease in Tardbp mutant knockin mice (Aim 1) and determining the impact of Tardbp mutations on PV-IN properties and cortical E:I balance with age (Aim 2). Differential gene expression and splicing profiles will be generated for PV-INs and compared to other neuron types using cell-type-specific translating ribosome purification protocols, with comparison to publicly available datasets of transcriptional changes in mouse and iPSC models of FTLD-TDP and other FTDs and TDP-43 RNA-binding assay databases. Computer-assisted modeling will be used to generate cell-type-specific protein-protein-interaction networks to identify convergent genes/proteins which could serve as targets for preventing cellular dysfunction. Electrophysiological approaches will explore the contributions of different cell types to the progression of cortical dysfunction, with comparison to a TDP-43 overexpression model to explore whether altered neuronal properties reflect a gain-of-function mechanism. These studies have the potential to reveal the mechanisms by which TDP-43 abnormalities influence cortical function and identify novel genes and/or pathways for promoting normal cortical function in patients with FTD.

项目摘要额颞痴呆（FTD）是一种使人衰弱的，与年龄相关的神经退行性疾病。额颞叶变性（FTLD），通常伴随着累积和/或功能障碍蛋白质TDP-43（FTLD-TDP）。由TARDBP基因编码的TDP-43的汇总发生在有或没有的情况下 TARDBP中的伴随突变，表明其积累代表了收敛机制 FTD中的基本皮质脆弱性。 TDP-43的有害影响的基础机制功能障碍很复杂，可能涉及功能丧失机制，这是由于改变 TDP-43的细胞内隔室化和聚集特性。尽管有细胞培养和TDP-43病理学的小鼠模型，TARDBP突变产生的确切机制体内的皮质功能障碍和细胞损失尚不清楚。最近的成像研究暗示了患者皮质的兴奋性和抑制性（E：I）平衡的破坏使用FTD，探索体内产生的机制的工作很少。最新数据使用TDP-43的敲蛋白和过表达模型产生的已经揭示了基因表达的改变，表达快速加速的中间神经元（PV-INS）的功能和可行性，可提供的细胞皮质中喂养前gabaergic神经传递的主要来源，对于维持E：I至关重要平衡。但是，关于TARDBP的PV-IN漏洞的机制知之甚少体内突变以及PV-IN功能障碍如何促进金字塔兴奋性神经元功能和损失。这本应用程序中提出的实验旨在通过评估TDP-43突变对PV-IN的影响 TARDBP突变体疾病进展过程中发生的PV特异性转录变化敲击蛋白小鼠（AIM 1）并确定TARDBP突变对PV-IN特性和皮质E的影响：I 与年龄保持平衡（目标2）。将对PV-INS生成差异基因表达和剪接曲线，并且与其他使用细胞类型的翻译核糖体纯化方案相比，与其他神经元类型相比与FTLD-TDP的鼠标和IPSC模型中转录更改的公开可用数据集进行比较以及其他FTD和TDP-43 RNA结合测定数据库。计算机辅助建模将用于生成细胞类型特异性蛋白质 - 蛋白质相互作用网络，以鉴定可以融合的基因/蛋白质充当防止细胞功能障碍的靶标。电生理方法将探索与TDP-43相比，不同细胞类型对皮质功能障碍进展的贡献过表达模型以探索改变神经元特性是否反映了功能获得的机制。这些研究有可能揭示TDP-43异常影响皮质的机制功能并确定新型基因和/或途径，用于促进FTD患者的正常皮质功能。