Bruton's Tyrosine Kinase: A Potential Novel Target for Neurological Disorders

Abstract

Bruton's tyrosine kinase (BTK) is a crucial part of the B-cell receptor signaling pathway that has been extensively studied in various types of malignancies. Recent studies have extended our knowledge on its role in metabolism as well as neurological disorders. It may play an important role in the pathophysiology of neurological diseases, such as multiple sclerosis, Alzheimer's disease, brain injury, and several others. Activation of inflammasomes, mainly NLRP3, is one of the core mechanisms by which it promotes inflammation in the brain related to aging and diseases. In this paper, we provide an overview of the less explored roles of BTK in several brain diseases and discuss the potential of its inhibition to become a therapeutic target for neurological diseases.

Fig. 1

Structure of BTK and its interactions with other genes. BTK consists of 659 amino acids and contains five domains, from the N-terminus to the C-terminus; the domains are listed as the pleckstrin homology (PH) domain, proline-rich Tec homology (TH) domain, Src homology (SH) domain SH3, SH2, and catalytic domain. Four approved BTK inhibitors by the FDA mainly target the catalytic domain of BTK. Irreversible BTK inhibitors bind to C481, while reversible BTK inhibitors do not bind to C481, such as fenebrutinib, which forms hydrogen bonds with K430 and M477.

Fig. 2

Actions of ibrutinib on different cell types. Ibrutinib inhibits the phosphorylation of BTK, thereby inhibiting the activation of downstream signaling pathways (solid black lines). Ibrutinib shows off-target effects through the inhibition of additional kinases, including Tec, ITK, and EGFR. BTK, Bruton tyrosine kinase; EGFR, epidermal growth factor receptor; GpvI, glycoprotein VI; ITK, interleukin-2-inducible T-cell kinase; TEC, tyrosine kinase expressed in hepatocellular carcinoma.

Fig. 3

Association of BTK in B-cell receptor signaling. The creation of a microsignalosome made up of VAV, phosphoinositide 3-kinases (PI3K), BTK, leukocyte protein of 65 kDa (SLP65), and phosphor-lipase C2 (PLC2) is the outcome of B-cell receptor (BCR) signaling. BTK is primarily in charge of activating PLC2, which triggers an influx of Ca²⁺, the transcription factors nuclear factor-KB (NF-KB) and nuclear receptor of activated T cells (NFAT), and extracellular signal-regulated kinase (ERK1 or ERK2) activation. In addition, BTK activation causes the Wiskott-Aldrich syndrome protein (WASP) to become active, which results in cytoskeleton alterations linked to BCR activation. Ak strain trans-forming (AKT) is triggered by PI3K, which phosphorylates (P) forkhead box O (FOXO) transcription factors and renders them inactive, independent of Ca²⁺. AKT releases the BH3-only protein BCL-2 antagonist of cell death (BAD) from BCL-XL and stabilizes MCL1 by blocking proapoptotic proteins, including AKT. Actin-related protein, B-cell adapter for PI3K, BCL-2 interacting mediator of cell death. CARD11, protein 11 with a caspase recruitment domain; CIN85, an 85 kDa CBL-interacting protein; diacylglycerol, glycogen synthase kinase, calcineurin, and immunoglobulin, NF-KB kinase inhibitor, and Ig (immunoglobulin) IP3, phosphatidylinositol-3,4,5, trisphosphate; IP3R, the IP3 receptor; ITAM, the immunoreceptor tyrosine-based activation motif; MALT1, the mucosa-associated lymphoid tissue lymphoma translocation protein 1; PDK1, the 3-phosphoinositide-dependent protein kinase 1; PIP3, the phosphatidylinositol-3,4,5.

Fig. 4

Overview of immuno-modulatory mechanisms related to BTK inhibition. When BTK is inhibited within the CNS, it has various effects on the immune system. In B cells, inhibition of BTK reduces the ability to present antigens, produce antibodies, and generate proinflam-matory cytokines through pathways such as the BCR and TLR pathways. Additionally, BTK inhibition can decrease the proinflammatory profile, migration, and cytokine production of microglia. BTK inhibition also prevents the activation of the NLRP3 inflammasome in neurons, macro-phages, and neutrophils, which leads to a decrease in IL-1β production and ultimately provides neuroprotection.