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TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann–Pick type C1, and Batten disease
EMBO Molecular Medicine ( IF 11.1 ) Pub Date : 2022-08-05 , DOI: 10.15252/emmm.202115377
Anna Scotto Rosato 1 , Einar K Krogsaeter 1 , Dawid Jaślan 1 , Carla Abrahamian 1 , Sandro Montefusco 2 , Chiara Soldati 2 , Barbara Spix 1 , Maria Teresa Pizzo 2 , Giuseppina Grieco 2 , Julia Böck 1 , Amanda Wyatt 3 , Daniela Wünkhaus 4 , Marcel Passon 1 , Marc Stieglitz 5 , Marco Keller 5 , Guido Hermey 6 , Sandra Markmann 4 , Doris Gruber-Schoffnegger 4 , Susan Cotman 7 , Ludger Johannes 8 , Dennis Crusius 9 , Ulrich Boehm 3 , Christian Wahl-Schott 10 , Martin Biel 5 , Franz Bracher 5 , Elvira De Leonibus 2, 11 , Elena Polishchuk 2 , Diego L Medina 2, 12 , Dominik Paquet 9, 13 , Christian Grimm 1
Affiliation  

Lysosomes are cell organelles that degrade macromolecules to recycle their components. If lysosomal degradative function is impaired, e.g., due to mutations in lysosomal enzymes or membrane proteins, lysosomal storage diseases (LSDs) can develop. LSDs manifest often with neurodegenerative symptoms, typically starting in early childhood, and going along with a strongly reduced life expectancy and quality of life. We show here that small molecule activation of the Ca2+-permeable endolysosomal two-pore channel 2 (TPC2) results in an amelioration of cellular phenotypes associated with LSDs such as cholesterol or lipofuscin accumulation, or the formation of abnormal vacuoles seen by electron microscopy. Rescue effects by TPC2 activation, which promotes lysosomal exocytosis and autophagy, were assessed in mucolipidosis type IV (MLIV), Niemann–Pick type C1, and Batten disease patient fibroblasts, and in neurons derived from newly generated isogenic human iPSC models for MLIV and Batten disease. For in vivo proof of concept, we tested TPC2 activation in the MLIV mouse model. In sum, our data suggest that TPC2 is a promising target for the treatment of different types of LSDs, both in vitro and in-vivo.

中文翻译:

TPC2 挽救 IV 型粘脂病、Niemann-Pick C1 型和 Batten 病的溶酶体储存

溶酶体是降解大分子以回收其成分的细胞器。如果溶酶体降解功能受损,例如,由于溶酶体酶或膜蛋白的突变,可能会发展为溶酶体贮积病 (LSD)。LSDs 通常表现为神经退行性症状,通常从儿童早期开始,并伴随着预期寿命和生活质量的大幅降低。我们在这里展示了 Ca 2+的小分子活化可渗透的内溶酶体双孔通道 2 (TPC2) 可改善与 LSD 相关的细胞表型,例如胆固醇或脂褐质积聚,或电子显微镜观察到的异常空泡的形成。TPC2 激活促进溶酶体胞吐作用和自噬的拯救效果在 IV 型粘液脂沉积症 (MLIV)、Niemann-Pick C1 型和 Batten 病患者成纤维细胞以及源自新生成的 MLIV 和 Batten 等基因人类 iPSC 模型的神经元中进行了评估疾病。对于体内概念验证,我们在 MLIV 小鼠模型中测试了 TPC2 激活。总之,我们的数据表明,TPC2 是治疗不同类型 LSD(体外体内)的有希望的靶点。
更新日期:2022-08-05
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