Basement membrane collagens and disease mechanisms

Abstract

Basement membranes (BMs) are specialised extracellular matrix (ECM) structures and collagens are a key component required for BM function. While collagen IV is the major BM collagen, collagens VI, VII, XV, XVII and XVIII are also present. Mutations in these collagens cause rare multi-systemic diseases but these collagens have also been associated with major common diseases including stroke. Developing treatments for these conditions will require a collective effort to increase our fundamental understanding of the biology of these collagens and the mechanisms by which mutations therein cause disease. Novel insights into pathomolecular disease mechanisms and cellular responses to these mutations has been exploited to develop proof-of-concept treatment strategies in animal models. Combined, these studies have also highlighted the complexity of the disease mechanisms and the need to obtain a more complete understanding of these mechanisms. The identification of pathomolecular mechanisms of collagen mutations shared between different disorders represent an attractive prospect for treatments that may be effective across phenotypically distinct disorders.

Increased Immunosignals of Collagen IV and Fibronectin Indicate Ischemic Consequences for the Neurovascular Matrix Adhesion Zone in Various Animal Models and Human Stroke Tissue

“…Overall, this study identified significantly enhanced immunosignals for collagen IV and fibronectin following focal cerebral ischemia in mice, rats, sheep, and in human stroke tissue. Derived from the observed close regional association of collagen IV and fibronectin -and considering their primary locations with reference to the basement membrane and the adjoined ECM Singh et al, 2010;Gatseva et al, 2019) -this study provides robust evidence for an ischemia-induced critical affection of the NMZ. Given the fact of the assumed highly dynamic situation at this site, different patterns of the collagen IV and especially the fibronectin immunosignal would have been expected over time.…”

“…Using multiple immunofluorescence approaches to tissues affected by different durations of focal cerebral ischemia, a spatio-temporal characterization of collagen IV as the major part of the basement membrane (Thomsen et al, 2017;Gatseva et al, 2019), and fibronectin as a major component of the ECM (Singh et al, 2010;Mezzenga and Mitsi, 2019) was performed. To consider the phenomenon of a translational roadblock in the field of stroke research that was at least partially related to artificial models (Young et al, 2007;Endres et al, 2008), efforts have been made to use different animal models with individual strengths and weaknesses (Durukan and Tatlisumak, 2007) as well as different species for this study.…”

“…Among the subsumed non-cellular structures, the basement membrane is of special interest because of its close vicinity to the endothelial layer, leading to the assumption of an involvement in regulatory processes within the NVU and thus the BBB integrity (Reed et al, 2019;Xu et al, 2019). In addition to the proteins laminin, nidogen, and heparan sulfate proteoglycans, especially collagen isoforms with predominant collagen IV represent main components of the basement membranes (Thomsen et al, 2017;Gatseva et al, 2019). In this context, integrins were identified as transmembrane proteins with the two subunits α and ß linking the endothelial layer with the basement membrane (del Zoppo and .…”

Atypical basement membranes and basement membrane diversity – what is normal anyway?

“…Here, I have summarized our precarious knowledge of the mechanisms generating BM diversity and increased thickness or aggregate-like deposition in atypical structures. Importantly, changes in BM thickness are associated with diseases that affect the blood brain barrier, kidneys, cornea or retina (Chew and Lennon, 2018;Gatseva et al, 2019;Pozzi et al, 2017;Sekiguchi and Yamada, 2018). Furthermore, thick matrix deposits are seen in fibrotic conditions, where the expression of matrix proteins is upregulated, but the mechanisms that make that excess matrix form aberrant structures are unknown.…”

Dynamic protein quantitation (DyProQ) of procollagen-I by CRISPR-Cas9 NanoLuciferase tagging

“…DyProQ could also be used to study the biosynthesis of other collagens, e.g. collagen-II and collagen-XI in Stickler syndrome, collagen-III and collagen-V in the Ehlers Danlos syndrome, collagen-VI in Ullrich congenital muscular dystrophy and Bethlem myopathy, collagen-VII in epidermolysis bullosa, and collagen-IV in sporadic cerebral small vessel disease 46 and major common diseases including stroke (reviewed by 47 ). DyProQ has wide-ranging applications in studies of other proteins that are expressed at levels too low to be detected by fluorescent protein tagging of the endogenous protein.…”