Department of Integrative Biology, University of Wisconsin-Madison, Madison, WI 53706, USA.
Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA.
Dis Model Mech. 2022 Aug 1;15(8). doi: 10.1242/dmm.049422. Epub 2022 Aug 29.
Neurofibromatosis type 1 (NF1) is an autosomal-dominant neurogenetic disorder caused by mutations in the gene neurofibromin 1 (NF1). NF1 predisposes individuals to a variety of symptoms, including peripheral nerve tumors, brain tumors and cognitive dysfunction. Cognitive deficits can negatively impact patient quality of life, especially the social and academic development of children. The neurofibromin protein influences neural circuits via diverse cellular signaling pathways, including through RAS, cAMP and dopamine signaling. Although animal models have been useful in identifying cellular and molecular mechanisms that regulate NF1-dependent behaviors, translating these discoveries into effective treatments has proven difficult. Clinical trials measuring cognitive outcomes in patients with NF1 have mainly targeted RAS signaling but, unfortunately, resulted in limited success. In this Review, we provide an overview of the structure and function of neurofibromin, and evaluate several cellular and molecular mechanisms underlying neurofibromin-dependent cognitive function, which have recently been delineated in animal models. A better understanding of neurofibromin roles in the development and function of the nervous system will be crucial for identifying new therapeutic targets for the various cognitive domains affected by NF1.
神经纤维瘤病 1 型（NF1）是一种常染色体显性遗传神经发育障碍，由神经纤维瘤蛋白 1（NF1）基因的突变引起。NF1 使个体易患多种症状，包括周围神经肿瘤、脑肿瘤和认知功能障碍。认知缺陷会对患者的生活质量产生负面影响，尤其是儿童的社交和学业发展。神经纤维瘤蛋白通过多种细胞信号通路影响神经回路，包括 RAS、cAMP 和多巴胺信号通路。尽管动物模型在确定调节 NF1 依赖性行为的细胞和分子机制方面非常有用，但将这些发现转化为有效的治疗方法却证明很困难。测量 NF1 患者认知结果的临床试验主要针对 RAS 信号，但不幸的是，结果收效甚微。在这篇综述中，我们概述了神经纤维瘤蛋白的结构和功能，并评估了最近在动物模型中阐明的 NF1 依赖性认知功能的几种细胞和分子机制。更好地了解神经纤维瘤蛋白在神经系统发育和功能中的作用对于确定受 NF1 影响的各种认知领域的新治疗靶点至关重要。
