Collagen Proteostasis in Heath and Disease

Massachusetts Institute Of Technology, Cambridge MA

Investigators

Linked publications, trials & patents

Abstract

Collagen is the most abundant protein in animals, constituting up to one-third of total protein in humans. As the major proteinaceous component of tissues ranging from bone and skin to cartilage and basement mem- branes, it constitutes the molecular scaffold for animal life. This ubiquitous protein is challenging for cells to produce, requiring highly coordinated intracellular processes of folding, assembly, and quality control. Owing to the hierarchical nature of collagenous extracellular matrices, the physical and biochemical properties of these tissues are fundamentally defined by these upstream, intracellular processes. Defects, whether genetic or oth- erwise, that are detrimental to any aspect of collagen proteostasis can impact cell health or function and propa- gate to extracellular matrices, leading to diseases known as the collagenopathies. Unfortunately, these dis- eases almost universally lack effective, disease-modifying therapies. Current therapeutic strategies for the collagenopathies focus on regenerative therapies, efforts to strengthen the extracellular matrix itself, or palliative care. None of these approaches aim to address the up- stream issue leading to disease: a failure to properly fold and quality control collagen molecules themselves. If the breakdown of collagen proteostasis could be effectively addressed, the downstream symptoms targeted by current clinical strategies would be alleviated. Indeed, proteostasis enhancement has proven remarkably effi- cacious in many other genetic disorders, including cystic fibrosis, but it has yet to make serious inroads in the collagenopathies. One obstacle is inadequate understanding of the critical decision points in the collagen pro- teostasis network. Another issue is the challenge of pre-clinical testing of proteostasis-targeted interventions in a disease that requires robust, yet biochemically amenable, tissue model systems for discovery efforts. This R01 proposal seeks to address these knowledge gaps, both identifying and elucidating key mech- anisms of intracellular folding and quality control and assessing the therapeutic potential of proteostasis net- work-targeted therapeutics in the collagenopathies. In Aim 1, the functions of the highly conserved procollagen N-glycan in promoting folding, enabling quality control, and identifying when folded procollagens are ready for secretion will be elucidated, via comprehensive work both in cells and in vivo that will reveal the molecular mechanisms of collagen glycoproteostasis. The expectation is demonstration that the long-ignored procollagen N-glycan is actually the critical fulcrum of collagen proteostasis. In Aim 2, a state-of-the-art cartilage-in-a-dish model system is deployed to enable robust testing of proteostasis network-targeted therapies for the colla- genopathies. Combined with mechanistic studies to elucidate the biochemistry of dysregulated collagen prote- ostasis, work in this Aim will provide a strong foundation for a new, proteostasis-focused perspective on treat- ing the collagenopathies.