Perlecan: a review of its role in neurologic and musculoskeletal disease

Abstract

Perlecan is a 500 kDa proteoglycan residing in the extracellular matrix of endothelial basement membranes with five distinct protein domains and three heparan sulfate chains. The complex structure of perlecan and the interaction it has with its local environment accounts for its various cellular and tissue-related effects, to include cartilage, bone, neural and cardiac development, angiogenesis, and blood brain barrier stability. As perlecan is a key contributor to extracellular matrix health involved in many tissues and processes throughout the body, dysregulation of perlecan has the potential to contribute to various neurological and musculoskeletal diseases. Here we review key findings associated with perlecan dysregulation in the context of disease. This is a narrative review article examining perlecan’s role in diseases of neural and musucloskeletal pathology and its potential as a therapeutic index. Literature searches were conducted on the PubMed database, and were focused on perlecan’s impact in neurological disease, to include ischemic stroke, Alzheimer’s Disease (AD) and brain arteriovenous malformation (BAVM), as well as musculoskeletal pathology, including Dyssegmental Dysplasia Silverman-Handmaker type (DDSH), Schwartz-Jampel syndrome (SJS), sarcopenia, and osteoarthritis (OA). PRISMA guidelines were utilized in the search and final selection of articles.Increased perlecan levels were associated with sarcopenia, OA, and BAVM, while decreased perlecan was associated with DDSH, and SJS. We also examined the therapeutic potential of perlecan signaling in ischemic stroke, AD, and osteoarthritic animal models. Perlecan experimentally improved outcomes in such models of ischemic stroke and AD, and we found that it may be a promising component of future therapeutics for such pathology. In treating the pathophysiology of sarcopenia, OA, and BAVM, inhibiting the effect of perlecan may be beneficial. As perlecan binds to both α-5 integrin and VEGFR2 receptors, tissue specific inhibitors of these proteins warrant further study. In addition, analysis of experimental data revealed promising insight into the potential uses of perlecan domain V as a broad treatment for ischemic stroke and AD. As these diseases have limited therapeutic options, further study into perlecan or its derivatives and its potential to be used as novel therapeutic for these and other diseases should be seriously considered.

Integratingin silicopredictions with an engineered tissue assay identifies Perlecan as an age-perturbed re-quiescence cue for muscle stem cells

“…59 Perlecan whole-KO mice exhibit perturbed development of the skeletal system, and while they do initially form basement membranes, these are unstable and rapidly deteriorate due to shear stresses, particularly in the heart and vasculature. 53,60,61 With the interpretation that Perlecan is a requiescence cue for MuSCs during regeneration, the predicted phenotype held true when a transient knockdown of the protein in vivo led to a surplus of myogenic cells going into 7 DPI and a reduction at the 14 DPI endpoint. Without Perlecan, transient amplifying myoblasts production was escalated at the expense of MuSC population maintenance.…”

“…It is a basement membrane building block containing receptor binding sites (for integrins and dystroglycan), and is also a major binder of growth factors. 16,[51][52][53][54] Along with other PGs, it interconnects the laminin and collagen IV networks. 46,55 First identified in skeletal muscle just before the turn of the century, Perlecan interacts with the myofiber sarcolemma via glycosylphosphatidylinositol anchors.…”

Dyssegmental dysplasia Rolland–Desbuquois type is caused by pathogenic variants in HSPG2 - a founder haplotype shared in five patients

“…Perlecan is a huge extracellular matrix (ECM) proteoglycan (~500 KDa) with five domains and three heparan sulfate chains at the N-terminal (Fig. 2A ) [ 17 ]. Domain I contains three Ser-Gly-Asp attachment sites for heparan sulfate chains, and one sperm, enterokinase, and agrin homology (SEA) module [ 18 , 19 ].…”

The Glycosaminoglycan Side Chains and Modular Core Proteins of Heparan Sulphate Proteoglycans and the Varied Ways They Provide Tissue Protection by Regulating Physiological Processes and Cellular Behaviour

“…Perlecan’s multifunctional properties have led to its proposal as a potential candidate of application in repair biology [ 160 , 277 ], as well as general health and well-being [ 278 ]. Perlecan has potential roles in neural stem cell niches [ 164 ]; it improves vascular repair in spinal cord injury [ 279 ] and neurologic disease [ 280 ]; and it has roles in the development of Alzheimers Disease (AD) [ 281 ].…”

“…Perlecan's multifunctional properties have led to its proposal as a potential candidate of application in repair biology [160,277], as well as general health and well-being [278]. Perlecan has potential roles in neural stem cell niches [164]; it improves vascular repair in spinal cord injury [279] and neurologic disease [280]; and it has roles in the development of Alzheimers Disease (AD) [281]. Abbreviations: CSPG4, melanoma-associated chondroitin sulfate proteoglycan, or neuron-glial antigen 2; PRELP, proline/arginine-rich end leucine-rich repeat protein, Prolargin; WARP, von Willebrand Factor A domain-related protein; FGF, Fibroblast growth factor; BMP, Bone morphogenetic protein; PDGF, Platelet derived growth factor; VEGF, Vascular cell endothelial cell growth factor; α-DG, alpha dystroglycan; IL, Interleukin; Ang-3, Angiopoietin like protein-3; G6b-B-R, Megakaryocyte lineage-specific immunoreceptor tyrosine-based inhibition motif-containing receptor; ECM-1, ECM protein-1; Acetyl Ch, acetyl cholinesterase.…”