Acta Neuropathologica

, Volume 136, Issue 1, pp 111–125 | Cite as

CADASIL brain vessels show a HTRA1 loss-of-function profile

  • Andreas Zellner
  • Eva Scharrer
  • Thomas Arzberger
  • Chio Oka
  • Valérie Domenga-Denier
  • Anne Joutel
  • Stefan F. Lichtenthaler
  • Stephan A. Müller
  • Martin Dichgans
  • Christof HaffnerEmail author
Original Paper


Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and a phenotypically similar recessive condition (CARASIL) have emerged as important genetic model diseases for studying the molecular pathomechanisms of cerebral small vessel disease (SVD). CADASIL, the most frequent and intensely explored monogenic SVD, is characterized by a severe pathology in the cerebral vasculature including the mutation-induced aggregation of the Notch3 extracellular domain (Notch3ECD) and the formation of protein deposits of insufficiently determined composition in vessel walls. To identify key molecules and pathways involved in this process, we quantitatively determined the brain vessel proteome from CADASIL patient and control autopsy samples (n = 6 for each group), obtaining 95 proteins with significantly increased abundance. Intriguingly, high-temperature requirement protein A1 (HTRA1), the extracellular protease mutated in CARASIL, was found to be strongly enriched (4.9-fold, p = 1.6 × 10−3) and to colocalize with Notch3ECD deposits in patient vessels suggesting a sequestration process. Furthermore, the presence of increased levels of several HTRA1 substrates in the CADASIL proteome was compatible with their reduced degradation as consequence of a loss of HTRA1 activity. Indeed, a comparison with the brain vessel proteome of HTRA1 knockout mice (n = 5) revealed a highly significant overlap of 18 enriched proteins (p = 2.2 × 10−16), primarily representing secreted and extracellular matrix factors. Several of them were shown to be processed by HTRA1 in an in vitro proteolysis assay identifying them as novel substrates. Our study provides evidence for a loss of HTRA1 function as a critical step in the development of CADASIL pathology linking the molecular mechanisms of two distinct SVD forms.


CADASIL CARASIL Cerebral small vessel disease Proteomics HTRA1 Extracellular matrix 



We thank N. Ziesch, B. Lindner and A. Berghofer for excellent technical assistance. This study was supported by the Vascular Dementia Research Foundation (to MD), the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain, to MD and AJ), the European Union’s Horizon 2020 research and innovation program (SVDs@target, to MD), the Deutsche Forschungsgemeinschaft (FOR2290, to SL; DI 722/13-1, to MD; HA2448/6-1, to CH), the Helmholtz Israel program (to SL), the Centers of Excellence in Neurodegeneration (to SL), the Breuer foundation Award (to SL) and the National Research Agency of France (ANR-16-RHU RGE16212HKA, to AJ).

Author contributions

AZ, SM, ES, SL, MD and CH designed the project; SM and SL performed proteomic experiments; AZ and ES performed biochemical experiments; TA, CO, VDD and AJ contributed critical materials and expertise; AZ, SM, ES, SL, MD and CH analyzed data and wrote the manuscript; all authors reviewed and revised the manuscript.

Supplementary material

401_2018_1853_MOESM1_ESM.pdf (623 kb)
Supplementary material 1 (PDF 623 kb)
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Supplementary material 2 (XLSX 2186 kb)
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Supplementary material 3 (XLSX 2282 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Andreas Zellner
    • 1
  • Eva Scharrer
    • 1
  • Thomas Arzberger
    • 2
    • 3
  • Chio Oka
    • 4
  • Valérie Domenga-Denier
    • 5
    • 6
  • Anne Joutel
    • 5
    • 6
  • Stefan F. Lichtenthaler
    • 7
    • 8
    • 9
    • 10
  • Stephan A. Müller
    • 7
    • 8
  • Martin Dichgans
    • 1
    • 10
  • Christof Haffner
    • 1
    Email author
  1. 1.Institute for Stroke and Dementia ResearchKlinikum der Universität München, Ludwig-Maximilians-Universität MünchenMunichGermany
  2. 2.Center for Neuropathology and Prion ResearchLudwig-Maximilians-Universität MünchenMunichGermany
  3. 3.Department of Psychiatry and PsychotherapyLudwig-Maximilians-Universität MünchenMunichGermany
  4. 4.Laboratory of Gene Function in AnimalsNara Institute of Science and TechnologyIkomaJapan
  5. 5.Department of Genetics and Pathogenesis of Cerebrovascular DiseasesINSERM, UMRS 1161, Université Paris Diderot, Sorbonne Paris CitéParisFrance
  6. 6.DHU NeuroVascSorbonne Paris CitéParisFrance
  7. 7.German Center for Neurodegenerative Diseases (DZNE)MunichGermany
  8. 8.NeuroproteomicsSchool of Medicine, Klinikum rechts der Isar, Technische Universität MünchenMunichGermany
  9. 9.Institute for Advanced StudyTechnische Universität MünchenGarchingGermany
  10. 10.Munich Cluster for Systems Neurology (SyNergy)MunichGermany

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