Molekulare Mechanismen rezessiver und dominanter Mutationen in HTRA1 - einer Protease mit Krankheitsrelevanz bei zerebralen Mikroangiopathien

• Antragstellerinnen / Antragsteller: Dr. Nathalie Beaufort; Professor Dr. Martin Dichgans
• Fachliche Zuordnung: Molekulare und zelluläre Neurologie und Neuropathologie ; Klinische Neurologie; Neurochirurgie und Neuroradiologie ; Molekulare Biologie und Physiologie von Nerven- und Gliazellen
• Förderung: Förderung von 2017 bis 2021
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 320697423

• Erstellungsjahr: 2022

Zusammenfassung der Projektergebnisse

Mono- and bi-allelic loss-of-function mutations in the gene encoding the oligomeric protease HTRA1 cause familial cerebral small vessel disease, stroke and dementia. We combined in silico, in vitro and in vivo approaches (i) to investigate the mechanisms linking HTRA1 deregulation to brain vasculopathy and (ii) to design and assess intervention strategies. Through a combination of ex vivo and in vivo studies we unraveled how a set of diseasecausing point mutations interfere with the oligomeric assembly of HTRA1 and disrupt its enzymatic activity. We further established mechanistically distinct protein repair approaches to reverse these deleterious effects. Notably, we elucidated the consequences of an archetypal pathogenic mutation on the mouse cerebrovascular proteome and provide proof of concept for functional correction of HTRA1 in vivo. In addition, we demonstrated that beyond deleterious mutations linked to highly penetrant diseases, deregulation of HTRA1 has a broader role in brain vascular disorders. Collectively, our work provides novel insights into key features of HTRA1-related brain vasculopathies and opens perspectives for targeted protein repair approaches with potential therapeutic applications.

Projektbezogene Publikationen (Auswahl)

• CADASIL brain vessels show a HTRA1 loss‑of‑function profile. Acta Neuropathologica. 2018; 136(1):111-125
  A. Zellner, E. Scharrer, T. Arzberger, C. Oka, V. Domenga-Denier, A. Joutel, SF Lichtenthaler, S.A. Müller, M. Dichgans, C. Haffner
  
• Stroke genetics: discovery, biology, and clinical applications. Lancet Neurology. 2019; 18(6):587-599
  M. Dichgans, S. Pulit, J. Rosand
  
• Stroke Genetics: Turning Discoveries into Clinical Applications. Stroke. 2021; 52(9):2974-2982
  M. Dichgans, N. Beaufort, S. Debette, C.D. Anderson
  
• Wholeexome sequencing reveals a role of HTRA1 and EGFL8 in brain white matter hyperintensities. Brain. 2021; 144(9):2670-2682
  R. Malik, N. Beaufort, S. Frerich, B. Gesierich , M.K. Georgakis, K. Rannikmäe, A.C. Ferguson , C. Haffner, M. Traylor, M. Ehrmann, C.L.M. Sudlow, M. Dichgans
  
• Proteomic profiling in cerebral amyloid angiopathy reveals an overlap with CADASIL highlighting accumulation of HTRA1 and its substrates. Acta Neuropathologica Communications. 2022; 10(1):6
  A. Zellner, S.A. Müller, B. Lindner, N. Beaufort, A.J.M. Rozemuller, T. Arzberger, N.C. Gassen, S.F. Lichtenthaler, B. Kuster, C. Haffner, M. Dichgans