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.

Differential Proteome Profiling Analysis under Pesticide Stress by the Use of a Nano-UHPLC-MS/MS Untargeted Proteomic-Based Approach on a 3D-Developed Neurospheroid Model: Identification of Protein Interactions, Prognostic Biomarkers, and Potential Therapeutic Targets in Human IDH Mutant High-Grade Gliomas

“…They are involved in calcium homeostasis. A novel study conducted by Godinez et al (2022) has revealed that neuroserpin plays an important role in mediating neurite outgrowth and axonal development as well as in maintaining normal synaptic plasticity through its inhibitory effects on the tissue plasminogen activator (tPA) in the CNS, thereby preventing tPA interaction with the NMDA receptor-mediated calcium influx, which contributes to excitotoxic neuronal apoptosis. , The elevated expression of serpin superfamily proteins was associated with low survival and increased recurrence rates …”

“…141 Based on our findings, we can suggest other straightforward therapeutic strategies to counteract the growth of IDH mutant high-grade gliomas, such as inhibition of the neuroserpin effect, which mediates in correlation with p63, tumor growth, metastasis, and cellular survival; likewise, the activation of the plasmin proteolytic axis was involved in multiple metastaticsuppressive mechanisms, in particular, degradation of the axonal path-finding L1 cell-adhesion molecule (L1CAM) specifically expressed by metastatic cancer cells during their invasion of the brain parenchyma and capillaries. 95 Moreover, the increased expression of cystatins involved in apoptosis regulation elicited by oxidative stress is an attempt to counteract the autolytic properties of cathepsin(s). Thus, disturbing the balance between cystatin and cathepsin with targeted therapy can promote tumor cell death.…”

“…A novel study conducted by Godinez et al (2022) has revealed that neuroserpin plays an important role in mediating neurite outgrowth and axonal development as well as in maintaining normal synaptic plasticity through its inhibitory effects on the tissue plasminogen activator (tPA) in the CNS, thereby preventing tPA interaction with the NMDA receptor-mediated calcium influx, which contributes to excitotoxic neuronal apoptosis. 95,96 The elevated expression of serpin superfamily proteins was associated with low survival and increased recurrence rates. 97 Another identified protein encoded by CAMK (2A, 2B, 2D) is a member of the N-methyl-D-aspartate receptor (NMDAR) signaling complex in excitatory synapses regulating the NMDAR-dependent potentiation of the AMPA receptor and therefore excitatory synaptic transmission.…”

The probable role of tissue plasminogen activator/neuroserpin axis in Alzheimer’s disease: a new perspective

“…Markedly, neuroserpin polymorphism and dysfunction trigger its intracellular accumulation with the development of wide-spectrum diseases like familial encephalopathy with neuroserpin inclusion body (FENIB) [ 69 ]. Alterations in the expression and activity of neuroserpins are associated with the development of different neuropathological disorders.…”

“…Genetic variations of neuroserpin expression are linked with the development of various neurological disorders, including FENIB, myoclonic epilepsy, AD, cancer, and glaucoma (Fig. 5 ) [ 69 ].

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