Kinarivala Nihar, Morsy Ahmed, Patel Ronak, Carmona Angelica V, Sajib Md Sanaullah, Raut Snehal, Mikelis Constantinos M, Al-Ahmad Abraham, Trippier Paul C
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, United States.
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
ACS Pharmacol Transl Sci. 2020 Sep 1;3(5):931-947. doi: 10.1021/acsptsci.0c00077. eCollection 2020 Oct 9.
The neuronal ceroid lipofuscinoses (NCLs) are a family of rare lysosomal storage disorders. The most common form of NCL occurs in children harboring a mutation in the gene. This form is lethal with no existing cure or treatment beyond symptomatic relief. The pathophysiology of CLN3 disease is complex and poorly understood, with current and models failing to identify pharmacological targets for therapeutic intervention. This study reports the characterization of the first CLN3 patient-specific induced pluripotent stem cell (iPSC)-derived model of the blood-brain barrier and establishes the suitability of an iPSC-derived neuron model of the disease to facilitate compound screening. Upon differentiation, hallmarks of CLN3 disease are apparent, including lipofuscin and subunit c of mitochondrial ATP synthase accumulation, mitochondrial dysfunction, and attenuated Bcl-2 expression. The model led to the identification of small molecules that cleared subunit c accumulation by mTOR-independent modulation of autophagy, conferred protective effects through induction of Bcl-2 and rescued mitochondrial dysfunction.
神经元蜡样脂褐质沉积症（NCLs）是一类罕见的溶酶体贮积症。最常见的NCL形式发生在携带该基因突变的儿童中。这种形式是致命的，除了缓解症状外，没有现有的治愈方法或治疗手段。CLN3疾病的病理生理学很复杂，人们了解甚少，目前的细胞和动物模型未能确定用于治疗干预的药理学靶点。本研究报告了首个CLN3患者特异性诱导多能干细胞（iPSC）衍生的血脑屏障模型的特征，并确定了该疾病的iPSC衍生神经元模型在促进化合物筛选方面的适用性。分化后，CLN3疾病的特征很明显，包括脂褐质和线粒体ATP合酶亚基c的积累、线粒体功能障碍以及Bcl-2表达减弱。该模型导致鉴定出了通过自噬的mTOR非依赖性调节清除亚基c积累、通过诱导Bcl-2赋予保护作用并挽救线粒体功能障碍的小分子。
