Molecular mechanisms of recessive and dominant mutations in the small vessel disease-related high temperature requirement protease HTRA1
Clinical Neurology; Neurosurgery and Neuroradiology
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
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.
Publications
- 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
(See online at https://doi.org/10.1007/s00401-018-1853-8) - Stroke genetics: discovery, biology, and clinical applications. Lancet Neurology. 2019; 18(6):587-599
M. Dichgans, S. Pulit, J. Rosand
(See online at https://doi.org/10.1016/s1474-4422(19)30043-2) - Stroke Genetics: Turning Discoveries into Clinical Applications. Stroke. 2021; 52(9):2974-2982
M. Dichgans, N. Beaufort, S. Debette, C.D. Anderson
(See online at https://doi.org/10.1161/strokeaha.121.032616) - 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
(See online at https://doi.org/10.1093/brain/awab253) - 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
(See online at https://doi.org/10.1186/s40478-021-01303-6)
