Papp Diána, Kovács Tibor, Billes Viktor, Varga Máté, Tarnóci Anna, Hackler László, Puskás László G, Liliom Hanna, Tárnok Krisztián, Schlett Katalin, Borsy Adrienn, Pádár Zsolt, Kovács Attila L, Hegedűs Krisztina, Juhász Gábor, Komlós Marcell, Erdős Attila, Gulyás Balázs, Vellai Tibor
a Velgene Biotechnology Research Ltd. , Szeged , Hungary.
b Department of Genetics , Eötvös Loránd University , Budapest , Hungary.
Autophagy. 2016;12(2):273-86. doi: 10.1080/15548627.2015.1082023.
Autophagy is a major molecular mechanism that eliminates cellular damage in eukaryotic organisms. Basal levels of autophagy are required for maintaining cellular homeostasis and functioning. Defects in the autophagic process are implicated in the development of various age-dependent pathologies including cancer and neurodegenerative diseases, as well as in accelerated aging. Genetic activation of autophagy has been shown to retard the accumulation of damaged cytoplasmic constituents, delay the incidence of age-dependent diseases, and extend life span in genetic models. This implies that autophagy serves as a therapeutic target in treating such pathologies. Although several autophagy-inducing chemical agents have been identified, the majority of them operate upstream of the core autophagic process, thereby exerting undesired side effects. Here, we screened a small-molecule library for specific inhibitors of MTMR14, a myotubularin-related phosphatase antagonizing the formation of autophagic membrane structures, and isolated AUTEN-67 (autophagy enhancer-67) that significantly increases autophagic flux in cell lines and in vivo models. AUTEN-67 promotes longevity and protects neurons from undergoing stress-induced cell death. It also restores nesting behavior in a murine model of Alzheimer disease, without apparent side effects. Thus, AUTEN-67 is a potent drug candidate for treating autophagy-related diseases.
自噬是真核生物中消除细胞损伤的主要分子机制。维持细胞内稳态和功能需要基础水平的自噬。自噬过程中的缺陷与包括癌症和神经退行性疾病在内的各种年龄依赖性疾病的发生以及加速衰老有关。在遗传模型中，自噬的基因激活已被证明可以延缓受损细胞质成分的积累，延迟年龄依赖性疾病的发生，并延长寿命。这意味着自噬可作为治疗此类疾病的靶点。尽管已经鉴定出几种诱导自噬的化学试剂，但它们大多数在核心自噬过程的上游起作用，从而产生不良副作用。在这里，我们筛选了一个小分子文库，寻找MTMR14的特异性抑制剂，MTMR14是一种与肌管蛋白相关的磷酸酶，可拮抗自噬膜结构的形成，并分离出AUTEN-67（自噬增强剂-67），它能显著增加细胞系和体内模型中的自噬通量。AUTEN-67可延长寿命，并保护神经元免受应激诱导的细胞死亡。它还能恢复阿尔茨海默病小鼠模型中的筑巢行为，且无明显副作用。因此，AUTEN-67是治疗自噬相关疾病的有力候选药物。
