The small molecule AUTEN-99 (autophagy enhancer-99) prevents the progression of neurodegenerative symptoms

Abstract

Autophagy functions as a main route for the degradation of superfluous and damaged constituents of the cytoplasm. Defects in autophagy are implicated in the development of various age-dependent degenerative disorders such as cancer, neurodegeneration and tissue atrophy, and in accelerated aging. To promote basal levels of the process in pathological settings, we previously screened a small molecule library for novel autophagy-enhancing factors that inhibit the myotubularin-related phosphatase MTMR14/Jumpy, a negative regulator of autophagic membrane formation. Here we identify AUTEN-99 (autophagy enhancer-99), which activates autophagy in cell cultures and animal models. AUTEN-99 appears to effectively penetrate through the blood-brain barrier, and impedes the progression of neurodegenerative symptoms in Drosophila models of Parkinson’s and Huntington’s diseases. Furthermore, the molecule increases the survival of isolated neurons under normal and oxidative stress-induced conditions. Thus, AUTEN-99 serves as a potent neuroprotective drug candidate for preventing and treating diverse neurodegenerative pathologies, and may promote healthy aging.

Phosphoinositides in autophagy: current roles and future insights

“…Other studies show an important role for MTMRs in autophagy‐dependent clearance of dysfunctional proteins, making them attractive targets for neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s disease. For instance, inhibiting MTMR14/Jumpy using the small molecules such as autophagy enhancer 67 and autophagy enhancer 99 restores autophagic flux and reduces symptoms in Drosophila models for Parkinson’s and Huntington’s diseases (Table ).…”

Drosophilaegg-derived tyrosine phosphatase (EDTP): a novel target for improved survivorship to prolonged anoxia and cellular protein aggregates

“…These observations suggest a role for EDTP in the regulation of autophagy. This is indeed supported by the findings that PtdIns3P stimulates autophagy in human HT-29 cells [10], that MTMR14 negatively controls the autophagosome formation and maturation in mammalian cells [11], and that the EDTP/MTMR14 inhibitor, AUTEN-99, activates autophagy in human HeLa cells and mouse tissues [12]. Interestingly, the latter group also shows that overexpression of a modified EDTP (by skipping the first exon) in the fat body antagonizes the effect of AUTEN-67 in inducing autophagy [13].…”

“…EDTP/MTMR14 has two main functions: negative regulation of autophagy and disease-causing effect if deficient in the muscles [1,[11][12][13][14][15]. Drosophila EDTP has two peaks of expression, one Motoneurons are highly specialized and terminally differentiated with reduced function of global genome repair [32,33].…”

Tissue-specific downregulation ofEDTPsuppresses polyglutamine protein aggregates and extends lifespan inDrosophila

“…This observation suggests a role for EDTP in the regulation of autophagy. This is indeed supported by the findings that PtdIns3P stimulates autophagy in human HT-29 cells 9 , that mJUMPY negatively controls autophagosome formation and maturation in mammalian cells 10 , and that EDTP/JUMPY inhibitors, AUTEN-67 and AUTEN-99, activate autophagy in human cell lines and mouse tissues 11,12 .…”