AUTEN-67 (Autophagy Enhancer-67) Hampers the Progression of Neurodegenerative Symptoms in a Drosophila model of Huntington’s Disease

Billes, Viktor; Kovács, Tibor; Hotzi, Bernadette; Manzéger, Anna; Tagscherer, Kinga; Komlós, Marcell; Tarnóci, Anna; Pádár, Zsolt; Erdős, Attila; Bjelik, Annamária; Legradi, Adam; Gulya, Károly; Gulyás, Balázs; Vellai, Tibor

doi:10.3233/jhd-150180

Cited by 24 publications

(25 citation statements)

References 41 publications

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“…6b ”). Based on these data we can conclude that a significant portion of Ref(2)P/SQSTM1/p62 presents in an insoluble form in animals expressing 128Q-hHTT 35 . Nevertheless, the relative amount of Ref(2)P/SQSTM1/p62 was significantly decreased in 128Q-hHTT animals when they were treated with AUTEN-99 ( Fig.…”

Section: Resultsmentioning

confidence: 72%

“…AUTEN-99 also impeded the progression of neurodegenerative symptoms in Drosophila models of PD and HD ( Figs 5 and 6 ). These data suggest that AUTEN-99 serves as a potent drug candidate for preventing and treating various age-dependent neurodegenerative diseases, including the most prevalent ones such as PD and HD (see also refs 34 and 35 ).…”

Section: Discussionmentioning

confidence: 86%

“…The first molecule we characterized from the candidates is AUTEN-67 (autophagy enhancer-67). This agent is capable of delaying the onset and reducing the severity of pathological features observed in a mouse and a Drosophila model of Alzheimer’s and Huntington’s disease, respectively 34 35 . Based on cell culture experiments, AUTEN-67 exerts a potent neuroprotective effect 34 .…”

Section: Resultsmentioning

confidence: 99%

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

Kovács

Billes²,

Komlós³

et al. 2017

Sci Rep

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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.

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Section: Resultsmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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

Kovács

Billes²,

Komlós³

et al. 2017

Sci Rep

Self Cite

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“…Autophagy activated in transgenic knock-in mice expressing an artificial mutant form of huntingtin that lacked the polyglutamine repeat reportedly showed that increased expression of critical autophagy genes slowed down the age-dependent accumulation of damage in neurons and enhanced longevity in Drosophila melanogaster (Fleming et al, 2011). Autophagy enhancer-67 was reported to reduce (128Q) hHTT protein levels in the brain of HD Drosophila (Billes et al, 2016). In addition, the expression of TFEB in the striatum of HDQ 175/Q7 mice degraded mHtt by increasing the activity of autophagy and lysosomes (Vodicka et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Escins Isolated from Aesculus chinensis Bge. Promote the Autophagic Degradation of Mutant Huntingtin and Inhibit its Induced Apoptosis in HT22 cells

et al. 2020

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The pathogenesis of Huntington's disease (HD), an inherited progressive neurodegenerative disease, is highly associated with the cytotoxicity-inducing mutant huntingtin (mHtt) protein. Emerging evidence indicates that autophagy plays a pivotal role in degrading aggregated proteins such as mHtt to enhance neuronal viability. In this study, by employing preparative high-performance liquid chromatography (pre-HPLC), ultra-high performance liquid chromatography diode-array-detector quadrupole time-of-flight mass spectrometry (UHPLC-DAD-Q-TOF-MS) and nuclear magnetic resonance (NMR), three escins, escin IA (EA), escin IB (EB) and isoescin IA (IEA), were isolated and identified from the seed of Aesculus chinensis Bge. (ACB). After EGFP-HTT74-overexpressing HT22 cells were treated with EA, EB and IEA at safe concentrations, the clearance of mHtt and mHtt-induced apoptosis were investigated by Western blot, immunofluorescence microscopy and flow cytometry methods. In addition, the autophagy induced by these escins in HT22 cells was monitored by detecting GFP-LC3 puncta, P62 and LC3 protein expression. The results showed that EA, EB and IEA could significantly decrease mHtt levels and inhibit its induced apoptosis in HT22 cells. In addition, these three saponins induced autophagic flux by increasing the ratio of RFP-LC3 to GFP-LC3, and by decreasing P62 expression. Among the tested escins, EB displayed the best autophagy induction, which was regulated via both the mTOR and ERK signaling pathways. Furthermore, the degradation of mHtt and the commensurate decrease in its cytotoxic effects by EA, EB and IEA were demonstrated to be closely associated with autophagy induction, which depended on ATG7. In conclusion, we are the first to report that the escins, including EA, EB and IEA are novel autophagy inducers that degrade mHtt and inhibit mHtt-induced apoptosis in vitro and in vivo. As a result of these findings, the triterpenoid saponins in ACB might be considered to be promising candidates for the treatment of HD in the future.

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“…ENC1 knockdown data illustrated relief in mHtt induced neuronal death (Lee et al, 2016 ). In recent development on transgenic Drosophila , treatment with autophagy-enhancing molecule, AUTEN-67, caused impediment in HD symptoms (Billes et al, 2016 ).…”

Section: Remediation Of Neurodegeneration By Targeting Upr mentioning

confidence: 99%

Entanglement of UPRER in Aging Driven Neurodegenerative Diseases

Rahman

Jan

Ayyagarí

et al. 2017

Front. Aging Neurosci.

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The endoplasmic reticulum (ER) is an indispensable cellular organelle that remains highly active in neuronal cells. The ER bears the load of maintaining protein homeostasis in the cellular network by managing the folding of incoming nascent peptides; however, the stress imposed by physiological/environmental factors can cause ER dysfunctions that lead to the activation of ER unfolded protein response (UPRER). Aging leads to deterioration of several cellular pathways and therefore weakening of the UPRER. The decline in functioning of the UPRER during aging results in accumulation of misfolded proteins that becomes intracellular inclusions in neuronal cells, resulting in toxicity manifested as neurodegenerative diseases. With ascension in cases of neurodegenerative diseases, understanding the enigma behind aging driven UPRER dysfunction may lead to possible treatments.

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AUTEN-67 (Autophagy Enhancer-67) Hampers the Progression of Neurodegenerative Symptoms in a Drosophila model of Huntington’s Disease

Abstract: These results imply that AUTEN-67 impedes the progression of neurodegenerative symptoms characterizing HD, and that autophagy is a promising therapeutic target for treating this pathology. In humans, AUTEN-67 may have the potential to delay the onset and decrease the severity of HD.

Cited by 24 publications

References 41 publications

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

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

Escins Isolated from Aesculus chinensis Bge. Promote the Autophagic Degradation of Mutant Huntingtin and Inhibit its Induced Apoptosis in HT22 cells

Entanglement of UPRER in Aging Driven Neurodegenerative Diseases

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