Mechanisms of Thalamocortical Dysfunction and Social Deficits in FTD due to GRN Mutations

GRN 突变导致 FTD 丘脑皮质功能障碍和社交缺陷的机制

• 批准号: 10655613
• 负责人: Andrew Emmett Arrant
• 金额: $ 41.54万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655613
• 关键词: Address; Adverse effects; Age; Age Months; Alzheimer' s Disease; Antiinflammatory Effect; Behavior; Behavioral; Cathepsins; Cathepsins B; Complex; Cytoplasm; Dendrites; FOS gene; Fluorescent Dyes; Frontotemporal Dementia; Functional disorder; Genetic; Genetic Polymorphism; Goals; Growth; Impairment; Knowledge; Lentivirus Vector; Lysosomes; Measures; Medial; Mediating; Microinjections; Modeling; Molecular; Mus; Mutation; Neurites; Neurons; Nuclear; PGRN gene; Pathogenesis; Pathogenicity; Pathology; Patients; Prefrontal Cortex; Risk; Risk Reduction; Safety; Signal Transduction; Site; Social Behavior; Social Dominance; Structure; Testing; Thalamic structure; Therapeutic; Transgenic Mice; Tumor Promotion; Ubiquitin; Vertebral column; Viral Vector; Work; axon growth; cell type; design; efficacy evaluation; extracellular; immunoreaction; improved; insight; loss of function; minimal risk; mouse model; neural circuit; neuron loss; novel; pleiotropism; protein TDP-43; social deficits; targeted treatment; trafficking; treatment strategy; tumor growth; vector

Project Summary/Abstract Loss of function progranulin (GRN) mutations, most of which cause haploinsufficiency, are a major genetic cause of frontotemporal dementia (FTD) with TDP-43 pathology (FTD-TDP). Progranulin-boosting therapies are a promising treatment strategy, but the optimal progranulin-boosting strategy remains unclear. Progranulin has pleiotropic effects and undergoes complex trafficking and processing, so the distribution of progranulin across cell types and cellular compartments may determine the efficacy and safety of progranulin-boosting therapies. Optimal progranulin-boosting therapies would retain progranulin’s neurotrophic and anti- inflammatory effects, with minimal risk of adverse effects such as promotion of tumor growth. Design of such therapies is impeded by our limited understanding of the pathogenesis of FTD due to GRN mutations (FTD- GRN). Our prior work highlights loss of progranulin’s neurotrophic effects as an important mechanism of FTD- GRN. Restoring neuronal progranulin corrects FTD-related social deficits in Grn+/– mice, and selective loss of neuronal progranulin reproduces these deficits. Social deficits in Grn+/– mice are associated with loss of dendritic arborization in the medial prefrontal cortex (mPFC), which with the mediodorsal thalamus (MDt) forms a critical circuit for social dominance behavior. MDt-mPFC connectivity is impaired in Grn+/– mice, modeling impaired thalamocortical connectivity in symptomatic FTD-GRN patients. Understanding the molecular mechanism of progranulin’s neurotrophic effects may thus be crucial for design of optimal progranulin-boosting therapies, but it is unclear if these effects are mediated by extracellular signaling or by enhancing lysosomal activity. We therefore developed a lysosome-targeted progranulin (L-PGRN) viral vector that delivers progranulin to lysosomes without secretion. L-PGRN reproduced several neurotrophic effects of progranulin in cultured neurons, so we hypothesize that progranulin acts in lysosomes to maintain the structure of FTD- related thalamocortical circuitry, and that selectively delivering progranulin to lysosomes will correct FTD- related behavioral deficits and pathology. We will test this hypothesis in primary cortical neurons and mouse models. In aim 1, we will determine if progranulin promotes dendritic arborization by enhancing cathepsin activity. In aim 2, we will determine if progranulin acts in lysosomes to maintain FTD-related thalamocortical circuitry. In aim 3, we will use a novel Grn+/–:TDP-43 transgenic mouse cross to determine if selectively boosting lysosomal progranulin will correct FTD-related social deficits and pathology. These aims have the potential to advance our understanding of FTD-GRN pathogenesis, and may provide insight into FTD-TDP and Alzheimer’s disease (AD), as a GRN polymorphism increases risk for FTD-TDP and AD. These studies may also inform design of progranulin-boosting therapies by revealing lysosomes as progranulin’s key site of action. Selectively delivering progranulin to lysosomes could effectively treat FTD with lower risk of adverse effects.

项目摘要/摘要 功能原颗粒丧失(GRN)突变是一种主要的基因突变，其中大多数会导致单倍体功能不全 TDP-43致病因子额颞叶痴呆(FTD-TDP)。促颗粒原疗法 是一种很有前途的治疗策略，但最佳的前颗粒增强策略仍不清楚。普罗米林 具有多效性，并经历复杂的转运和加工，因此原颗粒的分布 跨细胞类型和细胞隔间可能决定原颗粒增强的有效性和安全性 治疗。最佳的原颗粒增强疗法将保留原颗粒的神经营养和抗- 炎症作用，不良反应的风险最小，如促进肿瘤生长。这样的设计 由于我们对GRN突变引起的FTD的发病机制了解有限，治疗受到阻碍。 GRN)。我们先前的工作强调了原颗粒的神经营养作用的丧失是FTD的一个重要机制。 GRN。恢复神经元原颗粒纠正GRN+/-小鼠FTD相关的社会缺陷，并选择性丢失 神经元原颗粒复制了这些缺陷。Grn+/-小鼠的社会缺陷与丧失 内侧前额叶皮质(MPFC)内的树突分支与丘脑内侧背侧核(MDT)形成 社会支配行为的关键环节。Grn+/-小鼠MDT-mPFC连接受损，模型 有症状的FTD-GRN患者丘脑皮质连接受损。理解分子 因此，原颗粒的神经营养作用机制可能是设计最佳原颗粒增强的关键。 治疗，但尚不清楚这些作用是通过细胞外信号还是通过增强溶酶体介导的 活动。因此，我们研制了一种溶酶体靶向原颗粒蛋白(L-pGRN)病毒载体，它可以传递 原颗粒到溶酶体，没有分泌物。L-前列环素复制了丙粒蛋白的几种神经营养作用 培养的神经元，因此我们假设原颗粒作用于溶酶体以维持FTD的结构- 相关的丘脑皮质回路，选择性地将原颗粒输送到溶酶体将纠正FTD- 相关的行为缺陷和病理学。我们将在原代大脑皮层神经元和小鼠身上测试这一假设 模特们。在目标1中，我们将确定原颗粒是否通过增强组织蛋白酶来促进树突的树枝形成。 活动。在目标2中，我们将确定原颗粒是否在溶酶体中起作用，以维持FTD相关的丘脑皮质 电路。在目标3中，我们将使用一个新的Grn+/-：TDP-43转基因小鼠杂交来确定是否选择性地 增加溶酶体原颗粒将纠正与FTD相关的社会缺陷和病理。这些目标具有 有可能促进我们对FTD-GRN发病机制的理解，并可能为FTD-TDP和 阿尔茨海默病(AD)，作为GRN基因的多态性，增加了FTD-TDP和AD的风险。这些研究可能 还通过揭示溶酶体作为原颗粒的关键作用部位，为原颗粒增强疗法的设计提供信息。 选择性地向溶酶体输送原颗粒可以有效地治疗FTD，且不良反应的风险较低。