Aegeline, a natural product from the plant Aegle marmelos, mimics the yeast SNARE protein Sec22p in suppressing α-synuclein and Bax toxicity in yeast

• Published in: Bioorganic & medicinal chemistry letters 2019-02, Vol.29 (3), p.454-460
• Main Authors: Derf, Asma, Sharma, Ankita, Bharate, Sandip B., Chaudhuri, Bhabatosh
• Format: Article
• Language: English
• Subjects: Aegeline; Aegle - chemistry; alpha-Synuclein - metabolism; Amides - chemistry; Amides - isolation & purification; Amides - pharmacology; Antioxidants - chemistry; Antioxidants - isolation & purification; Antioxidants - pharmacology; Apoptosis; Apoptosis - drug effects; bcl-2-Associated X Protein - metabolism; Biological Products - chemistry; Biological Products - isolation & purification; Biological Products - pharmacology; DNA-fragmentation; Dose-Response Relationship, Drug; Mitochondrial-membrane-potential; Molecular Structure; R-SNARE Proteins - antagonists & inhibitors; R-SNARE Proteins - metabolism; ROS; Saccharomyces cerevisiae - chemistry; Saccharomyces cerevisiae - cytology; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae Proteins - antagonists & inhibitors; Saccharomyces cerevisiae Proteins - metabolism; SEC22p; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.12.028

[Display omitted] 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.