Rare mutations in HTRA1 cause cerebral vasculopathy and stroke. Using in vitro, in silico and in vivo analyses, the Dichgans lab in collaboration with colleagues from Duisburg established mechanistically distinct protein repair approaches to reverse the deleterious effects of pathogenic mutations interfering with the oligomeric assembly and protease function of HTRA1. Their findings exemplify the feasibility of rational strategies to correct protein conformations and open perspectives for precision medicine.

Beaufort N, Ingendahl L, Merdanovic M, Schmidt A, Podlesainski D, Richter T, Neumann T, Kuszner M, Vetter IR, Stege P, Burston SG, Filipovic A, Ruiz-Blanco YB, Bravo-Rodriguez K, Mieres-Perez J, Beuck C, Uebel S, Zobawa M, Schillinger J, Malik R, Todorov-Völgyi K, Rey J, Roberti A, Hagemeier B, Wefers B, Müller SA, Wurst W, Sanchez-Garcia E, Zimmermann A, Hu XY, Clausen T, Huber R, Lichtenthaler SF, Schmuck C, Giese M, Kaiser M, Ehrmann M, Dichgans M. Rational correction of pathogenic conformational defects in HTRA1. Nat Commun. 2024 Jul 16;15(1):5944. doi: 10.1038/s41467-024-49982-8.