Prominent white matter related abnormalities associated with diverse molecular alterations in a mouse model of Col4a1 cerebral small vessel disease.

Brezzo, G.; Pokhilko, A.; Moss, J.; Koudelka, J.; Jansen, M. A.; Lennen, R.; Thompson, G.; Konstantinidou, S. M.; Yau, J.; Boland, E.; Williams, A.; Allan, S. M.; Granata, A.; Sinha, S.; Wang, T.; Markus, H. S.; Fisher, R.; Cader, M. Z.; Van Agtmael, T.; Horsburgh, K.

doi:10.1101/2025.04.04.647207

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bioRxiv · 10.1101/2025.04.04.647207

Prominent white matter related abnormalities associated with diverse molecular alterations in a mouse model of Col4a1 cerebral small vessel disease.

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Abstract

White matter abnormalities are a hallmark of cerebral small vessel disease (cSVD) and are closely linked to cognitive decline and dementia. However, despite their clinical importance, underlying mechanisms remain poorly understood. Collagen IV, encoded by genes COL4A1/COL4A2, is a major component of the basement membrane, a specialised extracellular matrix (ECM) structure. Mutations in these genes cause a genetic form of cSVD. We tested the hypothesis that ECM defects caused by a Col4a1 mutation lead to white matter pathology using an established mouse model of cSVD (Col4a1+/Svc). Behavioural testing with magnetic resonance diffusion tensor imaging, pathology and ultrastructural investigations of white matter were studied. The studies revealed that Col4a1+/Svc mice have cognitive impairments, reduced myelinating oligodendrocyte pools, axonal myelination defects, and altered white matter structural integrity. Proteomic analysis, of isolated white matter from Col4a1+/Svcmice, identified extensive changes to ECM composition and endoplasmic reticulum (ER) biology including ER stress induction. We also demonstrated that targeting protein folding to promote collagen secretion and reduce ER stress, increased myelinating oligodendrocytes and axon-glial integrity in Col4a1+/Svc mice. These data provide novel insight into the pathomolecular mechanisms of white matter abnormalities in cSVD and identify a modifiable pathway as a putative therapeutic target for cSVD.

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Brezzo, G., Pokhilko, A., Moss, J., Koudelka, J., Jansen, M. A., Lennen, R., Thompson, G., Konstantinidou, S. M., Yau, J., Boland, E., Williams, A., Allan, S. M., Granata, A., Sinha, S., Wang, T., Markus, H. S., Fisher, R., Cader, M. Z., Van Agtmael, T., Horsburgh, K.. 2025-04-04. Prominent white matter related abnormalities associated with diverse molecular alterations in a mouse model of Col4a1 cerebral small vessel disease.. https://doi.org/10.1101/2025.04.04.647207

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