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PRÉVENTION ET TRAITEMENT DE MALADIES NEURODÉGÉNÉRATIVES PAR ACTIVITÉ AUTOPHAGIQUE INDUITE PAR LIGAND OU PAR BIP ARGINYLÉE SE LIANT AU DOMAINE ZZ DE P62
专利权人:
Korea Research Institute of Bioscience and Biotechnology;Seoul National University R&DB Foundation
发明人:
KWON, Yong Tae,KIM, Bo Yeon,CHA, Hyunjoo,YOO, Young Dong,YU, Ji-eun
申请号：
EP16837234
公开号：
EP3338787A4
申请日:
2016.07.15
申请国别(地区):
EP
年份:
2018
代理人:
摘要：
The pharmacokinetics and key technologies of the present invention are summarized in Figure 1 . Particularly, malignant misfolded proteins such as mutant huntingtin and alpha-synuclein are coagulated and grow into oligomeric coagulum (‘ , ‘¡), fibrillar coagulum (‘¢) and eventually inclusion body (‘£). Young neurons produce a large amount of Nt-Arg through N-terminal arginylation (‘¤) of vesicle chaperones such as BiP secreted into the cytoplasm, and then arginylated BiP (R-BiP) is secreted binds to the misfolded proteins (‘¥). As a ligand, the Nt-Arg of R-BiP binds to the p62 ZZ domain (‘¦), and the normally inactivated closed form of p62 is changed to an open form, leading to structural activation (‘§). As a result, PB1 and LC3-binding domains are exposed. The PB1 domain induces oligomerization (‘¨), leading to the concentration as a p62 body (‘©) that is a coagulum capable of being degraded by autophagy. Then, p62 binds to LC3, which is protruding from the autopagosomal membranes, leading to the completion of autophagy targeting (‘ª) and lysosomal proteolysis. Since autophagy proteolysis including steps ‘¤-‘ª is strong in young neurons, cytotoxic protein coagulums (‘ -‘¤) do not accumulate. However in aged neurons, autophagy proteolysis including steps ‘¤-‘ª is weakened, and protein coagulums (‘ -‘¤) accumulate and become cytotoxic. In this invention, p62 is intentionally activated (‘«, ‘¬) by using low mass ligands of the p62 ZZ domain to effectively remove huntingtin and alpha-synuclein protein coagulums. Particularly, in step ‘«, p62 ligated with a ligand accelerates the oligomerization of p62-R-BiP-misfolded protein (‘¨) and the formation of autophagy coagulum (‘©). In step ‘¬, the ligand-p62 conjugate acts as an autophagy activator (‘) to induce the synthesis of LC3 and the conversion of LC3-I into LC3-II in order to accelerate the formation of autophagosomes (‘®).
来源网站：
中国工程科技知识中心
来源网址：
http://www.ckcest.cn/home/
