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

Abstract

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.

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Acknowledgements

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).

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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.

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Correspondence to Christof Haffner.

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Zellner, A., Scharrer, E., Arzberger, T. et al. CADASIL brain vessels show a HTRA1 loss-of-function profile. Acta Neuropathol 136, 111–125 (2018). https://doi.org/10.1007/s00401-018-1853-8

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Keywords

  • CADASIL
  • CARASIL
  • Cerebral small vessel disease
  • Proteomics
  • HTRA1
  • Extracellular matrix