Neuroserpin, a crucial regulator for axogenesis, synaptic modelling and cell-cell interactions in the pathophysiology of neurological disease

Abstract

Neuroserpin is an axonally secreted serpin that is involved in regulating plasminogen and its enzyme activators, such as tissue plasminogen activator (tPA). The protein has been increasingly shown to play key roles in neuronal development, plasticity, maturation and synaptic refinement. The proteinase inhibitor may function both independently and through tPA-dependent mechanisms. Herein, we discuss the recent evidence regarding the role of neuroserpin in healthy and diseased conditions and highlight the participation of the serpin in various cellular signalling pathways. Several polymorphisms and mutations have also been identified in the protein that may affect the serpin conformation, leading to polymer formation and its intracellular accumulation. The current understanding of the involvement of neuroserpin in Alzheimer's disease, cancer, glaucoma, stroke, neuropsychiatric disorders and familial encephalopathy with neuroserpin inclusion bodies (FENIB) is presented. To truly understand the detrimental consequences of neuroserpin dysfunction and the effective therapeutic targeting of this molecule in pathological conditions, a cross-disciplinary understanding of neuroserpin alterations and its cellular signaling networks is essential.

Keywords: Alzheimer’s disease; Glaucoma; Neuroserpin; Plasminogen; Retina; Serpin; Stroke; Tissue plasminogen activator.

Fig. 1

The role of neuroserpin in various diseases of the central nervous system. A flow diagram showing the involvement of neuroserpin in various disorders affecting the central nervous system. AT/RT, Atypical teratoid/rhabdoid tumours

Fig. 2

Neuroserpin crosstalk with cellular signalling pathways. A Neuroserpin is involved in cell adhesion via the regulation of N-cadherin expression. B Neuroserpin interacts with LRP (lipoprotein receptor-related protein) and may regulate localised proteolytic activity, cell adhesion, vascular permeability and neuronal protection against cell injury and death (dotted lines). C VLDL (very-low-density-lipoprotein) receptors have been shown to endocytose neuroserpin. It is hypothesised that neuroserpin may mediate reelin signalling leading to the activation of disabled-1 protein (Dab1). Dab1 interacts with the LDL (low-density lipoprotein) receptor and promotes intracellular tyrosine kinase signalling in brain and retina. D In stressed conditions, neuroserpin plays an important role in the activation of the Akt signalling, suppression of cell death (reduced lactose dehydrogenase release), prevention of apoptotic pathways induced by oxidative stress in neurons, and the activation of anti-apoptotic proteins. E Neuroserpin has been suggested to interact with NMDA (N-methyl-d-aspartate) receptors leading to reduction in Ca²⁺ influx and suppress excitotoxicity in neurons. Dotted lines in the figure indicate hypothesised functions, that have not been demonstrated experimentally

Fig. 3

Neuroserpin involvement in regulating amyloid β pathology. Schematic figure showing A neuroserpin binding to amyloid β fibrils leading to neuroserpin-Aβ complex formation. This neuroserpin-Aβ complex is resistant to plasmin proteolytic action and reduces the clearance of amyloid β deposits. B Increased neuroserpin binds to plasmin and makes the proteolytic enzyme unavailable to mediate clearance of amyloid β fibrils from the neuronal tissue

Fig. 4

Activation of ER signalling pathways in FENIB. Neuroserpin gene mutations have been associated with inducing endoplasmic reticulum stress response signalling. (1) Mutant neuroserpin polymers stimulate Ca²⁺ efflux from ER leading to I-kB activation and NF-kB mediated pro-inflammatory signalling. (2) Mutant neuroserpin is in part degraded by autophagy pathways through the formation of autophagosomes and their interaction with lysosomes. (3) Endoplasmic reticulum-associated degradation (ERAD) is able to eliminate mutant neuroserpin through proteasomal degradation (4) Mutant neuroserpin accumulation may lead to enhanced ER stress and activation of the unfolded protein response (UPR). These signalling mechanisms eventually lead to either the activation of protein degradation mechanisms or programmed cell death