TY - T1的病人派生细胞模型研究发病机理和开发治疗人类疾病引起的酸ceramidase缺乏症。乔(P1.139) JF -首页神经-神经学六世- 88 - 16补充SP - P1.139 AU -达里奥Ronchi盟费德里科•Ribaudo AU -马西莫·Aureli盟Domitilla Schiumarini AU -塞布丽娜Salani盟-西尔维亚Tartari AU -曼Garbellini AU - Bordoni Andreina盟达尼洛Tiziano AU -恩里科·贝尔蒂尼盟-诺阿Filosto盟Mirella Filocamo AU -桑德罗Sonnino AU -拉斐尔De Francesco盟-普螺旋器盟Nereo Bresolin AU - Giacomo Comi Y1 - 2017/04/18 UR - //www.ez-admanager.com/content/88/16_Supplement/P1.139.abstract N2 -目的:我们旨在建立特定的细胞模型等位基因的失调与肌阵挛癫痫脊髓性肌萎缩症(SMA-PME)和法伯的疾病。我们也研究疾病发病机理和潜在的救援策略。背景:SMA-PME是一种罕见的疾病,肌肉无力,最后导致致命的呼吸道瘫痪和棘手的肌阵挛癫痫。影响患者港突变ASAH1酸ceramidase编码,神经酰胺的分解代谢的酶委托和复杂的鞘脂类在溶酶体。也ASAH1突变导致严重的小儿多系统表型,法伯lipogranulomatosis。突显出这些疾病发病的机制是未知的。设计/方法:在这里,我们进行了大量的成纤维细胞的分子和生化特性获得5 SMA-PME和3法伯的病人。结果:控制相比,蛋白质分析记录改变表达式和酸ceramidase和减少其他成熟的稳定溶酶体酶包括酸性麦芽糖酶和组织蛋白酶d受损ceramidase活动和神经酰胺酸积累在患者被发现,这些改变在最严重的临床表现更为明显。鞘脂类代谢的差异基因表达分析披露的关键。标记的细胞凋亡是不变的。 Conversely, we observed late-stage autophagy impairment and altered lysosomal distribution. Pharmacological induction of autophagy improved the maturation of lysosomal enzymes with minimal effects on the availability of their active forms. A therapeutic approach based on small drugs chaperoning is currently ongoing: preliminary findings have shown a remarkable improvement of acid ceramidase stability in SMA-PME cells.We also derived induced pluripotent stem cell lines from ASAH1-mutated patients, which will be used to derive motor neurons as a model to investigate neurodegeneration associated with acid ceramidase dysfunction.Conclusions: Patients fibroblasts are useful to prove the pathogenicity of ASAH1 and helped to disclose novel mechanisms underlining acid ceramidase deficiency. Our findings demonstrated in vitro potential for pharmacological chaperone therapy for SMA-PME.Study Supported by: Telethon Exploratory Grant GEP14049 (PI: D. Ronchi)Disclosure: Dr. Ronchi has nothing to disclose. Dr. Ribaudo has nothing to disclose. Dr. Aureli has nothing to disclose. Dr. Schiumarini has nothing to disclose. Dr. Salani has nothing to disclose. Dr. Tartari has nothing to disclose. Dr. Garbellini has nothing to disclose. Dr. Bordoni has nothing to disclose. Dr. Tiziano has nothing to disclose. Dr. Bertini has received personal compensation for activities with AveXis, Biogen, Roche, Novartis, and Edison Pharmaceuticals as an advisor and/or consultant. Dr. Bertini has receives research support from Telethon and Italian Ministry of Health. Dr. Filosto has nothing to disclose. Dr. Filocamo has nothing to disclose. Dr. Sonnino has nothing to disclose. Dr. De Francesco has nothing to disclose. Dr. Corti has nothing to disclose. Dr. Bresolin has nothing to disclose. Dr. Comi has nothing to disclose. ER -