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

White matter abnormalities are a central feature of cerebral small vessel disease (cSVD) and underpin cognitive impairment and dementia but their mechanistic link remains poorly understood. To provide insight we studied mice (Col4a1^+/Svc) with a mutation in the geneCol4a1as an established model of cSVD due to collagen IV mutations. Since collagen IV is a key component of the basement membrane, a specialised extracellular matrix structure (ECM), we hypothesised that theCol4a1mutation would disrupt the ECM and cause white matter abnormalities. Microstructural alterations in white matter were assessed using Magnetic Resonance diffusion tensor imaging (MR-DTI) in parallel with pathology and ultrastructural investigations of white matter. We determined that myelinating oligodendrocyte pools were reduced in parallel with prominent alterations in myelinated axons and white matter structural integrity inCol4a1^+/Svcmice. Proteomic analysis of white matter revealed a significant number (n=176) of differentially expressed proteins inCol4a1^+/Svccompared to controls. In particular pathways relating to the ECM and the endoplasmic reticulum (ER), including ER stress, were affected. We exploited this in a pre-clinical intervention study using the FDA-approved chemical chaperone 4-phenylbutyrate (PBA) to promote protein trafficking and reduce ER stress. PBA treatment inCol4a1^+/Svcmice conferred protection against white matter defects (increasing myelinating oligodendrocytes and improving axon-glial integrity) compared to untreatedCol4a1^+/Svcmice. These data provide novel insight into the diversity of pathomolecular mechanisms of white matter abnormalities in cSVD and identify a modifiable pathway as a putative therapeutic target for cSVD.