The Role of the Urokinase Receptor in Epilepsy, in Disorders of Language, Cognition, Communication and Behavior, and in the Central Nervous System

Abstract

As a key component of the plasminogen activation system, uPAR, the receptor for the plasminogen activator of the urokinase type, is involved in many physiological and pathological processes. Besides its classical roles, there has been increased evidence that uPAR or uPAR-associated pathways, participate in the development, in the functioning and in the pathology of the central nervous system. Qualitative and quantitative changes in the expressions of uPAR and of its canonical ligand uPA have been observed in a large variety of epileptic disorders, either in human or in animal models, as well as in other brain diseases (stroke and brain trauma, multiple sclerosis, Alzheimer's disease, cerebral malaria, HIV-associated leukoencephalopathy and encephalitis). The variety of such pathological conditions and the different brain areas and cell types involved, likely reflects the wide range and the complexity of the multiple and somehow intertwined pathophysiological mechanisms related with uPAR. In the mouse, the knock-out of the Upar-encoding gene (Plaur) leads to significant and nearly complete loss in parvalbumin-containing interneurons during brain development. This is associated with increased susceptibility to spontaneous and chemically-induced seizures and with increased anxiety and impaired social interactions. The recent identification of the novel uPAR ligand SRPX2 (Sushi repeat protein, X-linked 2) and the regulation of both the SRPX2 and PLAUR genes by transcription factor FOXP2 has shed novel and exciting insights into the role of uPAR-related molecular networks in rolandic epilepsy, in developmental verbal dyspraxia, in perisylvian polymicrogyria, and generally in disorders of the speech areas and circuits. uPAR, its regulators and partners, as well as other proteins containing Ly-6/uPAR/alpha-neurotoxin domains, represent key entry points for present and future studies not only on speech-related disorders but also on epilepsy and autism spectrum disorders.

Urokinase-type Plasminogen Activator (uPA) and its Receptor (uPAR) Promote Neurorepair in the Ischemic Brain

“…However, the expression of both, the ligand and its receptor, increases in neurons following different forms of injury. These findings are in line with observations by others indicating that the expression of uPAR increases within the first few hours of peripheral nerve [22] , spinal cord [23] and cortical neurons [6,13] injury, and has led to propose that uPAR is a marker of central nervous system damage and a potential therapeutic target to promote neurorepair.…”

Genome‐wide protein QTL mapping identifies human plasma kallikrein as a post‐translational regulator of serum uPAR levels

“…SNP rs4253238 is also a prevalent SNP (MAF=0.496; HapMap CEU population) making it a potential widespread regulator of scuPAR with relevance in multiple human conditions, although further studies are needed to identify the SNPs in the rs4253238 LD block that are functionally relevant. We therefore hypothesize that KLKB1‐mediated reduction of scuPAR as identified in this study may play an important role in scuPAR‐associated diseases, such as prostate (10) and breast (9) cancers, epilepsy (11), cardiovascular disease (12), and FSGS (24).…”

“…This membrane‐bound receptor is ubiquitously expressed on multiple cell types and tissues (6) and is implicated in a number of diseases, including asthma (7, 8), cancer (9, 10), epilepsy (11), and cardiovascular disease (12), suggesting an important biological role for this protein. This is further supported at the cellular level, where uPAR has been reported to be involved in efficient epithelial wound repair (8), neutrophil recruitment during cellular inflammation, tumor invasiveness, and metastasis (13, 14), especially in breast cancer (15).…”

Robust candidates for language development and evolution are significantly dysregulated in the blood of people with Williams syndrome

“…CNTNAP2 is a direct target of FOXP2, the renowned "language gene" (Vernes et al, 2008;Adam et al, 2017) and regulates language development in non-pathological populations too (Whitehouse et al 2011, Whalley et al 2011, Kos et al 2012. Also mice lacking Plaur have significantly fewer neocortical parvalbumin-containing GABAergic interneurons, this being associated with impaired social interactions (Bruneau and Szepetowski, 2011). PLAUR is a target of FOXP2 too (Roll et al 2010), but also an effector of SRPX2, another of FOXP2's targets (Royer-Zemmour et al 2008) and a candidate for speech dyspraxia (Roll et al 2006).…”