Aegeline, a natural product from the plant Aegle marmelos, mimics the yeast SNARE protein Sec22p in suppressing α-synuclein and Bax toxicity in yeast
Authors: Asma Derf
Sandip B Bharate
Ankita Sharma
Bhabatosh Chaudhuri
Journal: Bioorganic & medicinal chemistry letters (2019)
Discipline: CHEMISTRY
Keywords: Aegeline; Apoptosis; DNA-fragmentation; Mitochondrial-membrane-potential; ROS
Affiliations: Leicester School of Pharmacy, De Montfort University, Leicester LE1 9BH, UK., Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India., Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India. Electronic address: ., Leicester School of Pharmacy, De Montfort University, Leicester LE1 9BH, UK. Electronic address: .

Abstract:  Herein, we have identified yeast Sec22p (ySec22p), a SNARE protein essential for endoplasmic reticulum to Golgi trafficking, as a suppressor of Bax-induced yeast apoptosis and corroborated published observations that ySec22p suppresses α-synuclein's toxicity in yeast. It has been suggested that compounds which enhance expression, in neurons, of human homologues of ySec22p (Sec22Bp/Sec22p/Sec22A) would prevent synucleinopathies, such as Parkinson's disease. With the aim of finding a small molecule that would mimic ySec22p, a library of natural products consisting of 394-compounds was screened using yeast cells that express either human α-synuclein or human Bax. The antioxidant aegeline, an alkaloid-amide occurring in the leaves of the plant Aegle marmelos Correa, was the only molecule that overcame apoptosis induced by both α-synuclein and Bax in yeast. Besides, aegeline also prevented growth block in cells expressing the more toxic A53T α-synuclein mutant. Restoration of cell growth occurred through inhibition of increased ROS levels, mitochondrial membrane potential loss and nuclear DNA fragmentation, characteristics of apoptosis manifested in α-synuclein or Bax-expressing cells. These results highlight the importance of yeast systems to identify rapidly molecules that may prevent the onset of apoptosis that occurs in Parkinson's disease. 

Retracted: No

PubPeer comments:
 https: www.sciencedirect.com science article pii S0960894X19304354 Corrigendum Unfortunately, when this paper was first published, the panel 2 of Figure 3D, was incorrect. The correct Fig. 3 has been printed below. ![file] *** I believe this is the original figure ![file] , 
 The problem with the original 3D panel 2 was (I guess) that it was used by mistake from another experiment, as it appears in Fig 1F of [Derf et al (2019)] :  (F). 3-copy u03b1-syn bearing yeast cells grown, in the **absence (panel 1)** or presence of radicicol (panel 2), stained with Phloxine B. Below, marked with green boxes. ![file] ![file] Red boxes: There is still a conflict between the present 3D panel 1, and 1G panel 1 of the Bioorganic Chemistry paper.  3-copy u03b1-syn bearing yeast cells stained with **Hoechst 33,342 dye**. Panels 1 and 2 are controls; panel 1 shows that only a small percentage of cells are alive in SG medium (containing galactose) because of u03b1-syn expression, whereas in panel 2, most cells are alive in glucose-containing SD medium (because there is no u03b1-syn expression). In the presence of radicicol (panel 3), cells grown in galactosecontaining SG medium are resistant to the toxic effects of u03b1-syn , 
 Fig 1D.  (D) Levels of nuclear DNA fragmentation, a hallmark of apoptosis, in yeast cells25 (which express (i) 2-copies of u03b1-syn alone (row 4) and co-expressing ySec22p (row 5), and (ii) a copy of Bax alone (row 1) and co-expressing ySec22p (row 2) or hBcl-xL (row 3). ![file] Colored boxes indicate panels also present in Fig 2D, G of [Derf et al (2019)] :  (D) Nuclear DNA fragmentation, as observed using the TUNEL assay, in yeast cells expressing 2-copies of Invss-u03b2A4 in minimal SG medium (containing galactose), in the absence of any compound, (panel 1) and in the presence of radicicol (panel 2). ... (G) Nuclear DNA fragmentation, as observed using the TUNEL assay, in yeast cells expressing 1-copy of Bax in minimal SG medium containing galactose, in the absence of any compound, (panel 1) and in the presence of radicicol (panel 2). ![file] Labels do not appear to be consistent. Purple and brown boxes indicate images repeated within the Radicicol paper. , 
 The comments pertaining to this publication are related to the biological experiments (microscopy) which were conducted by authors, Asma Derf and mentored by Prof. Bhabatosh Chaudhuri at DeMontfort University UK. My group only provided the natural product, aegeline to Prof. Bhabatosh Chaudhuriu2019s group for biological investigations and performed molecular modeling study (Fig. 4). Thus, there are no clarifications against these comments from my side. At my end, these authors have been contacted via email and they will address the raised queries. ,