Proteomics and functional study reveal kallikrein-6 enhances communicating hydrocephalus

Lei Yuan,Fance Wei,Youming Lu,Pengqi Zhang,Dongdong Zou,Xin Chen,Xia Yang,Aijun Zhang

doi:10.1186/s12014-021-09335-9

Abstract

BackgroundCommunicating hydrocephalus (CH) is a common neurological disorder caused by a blockage of cerebrospinal fluid. In this study, we aimed to explore the potential molecular mechanism underlying CH development.MethodsQuantitative proteomic analysis was performed to screen the differentially expressed proteins (DEPs) between patients with and without CH. A CH rat model was verified by Hoechst staining, and the co-localization of the target protein and neuron was detected using immunofluorescence staining. Loss-of-function experiments were performed to examine the effect of KLK6 on the synapse structure.ResultsA total of 11 DEPs were identified, and kallikrein 6 (KLK6) expression was found to be significantly upregulated in patients with CH compared with that in patients without CH. The CH rat model was successfully constructed, and KLK6 was found to be co-localized with neuronal nuclei in brain tissue. The expression level of IL-1β, TNF-α, and KLK6 in the CH group was higher than that in the control group. After knockdown of KLK6 expression using small-interfering RNA (siRNA), the expression levels of synapsin-1 and PSD95 in neuronal cells were increased, and the length, number, and structure of synapses were significantly improved. Following siRNA interference KLK6 expression, 5681 differentially expressed genes (DEGs) were identified in transcriptome profile. The upregulated DEGs of Appl2, Nav2, and Nrn1 may be involved in the recovery of synaptic structures after the interference of KLK6 expression.ConclusionsCollectively, KLK6 participates in the development of CH and might provide a new target for CH treatment.

Highlights

Communicating hydrocephalus (CH), a common neurological disorder, is associated with cognitive decline and severe deterioration of the quality of life of patients
The abnormal decline in extracellular matrix protein in cerebrospinal fluid (CSF) is associated with various neurological diseases, such as subarachnoid hemorrhage (SAH) [11], stroke [12], and traumatic brain injury [13]. These findings suggest that kallikrein 6 (KLK6) plays a vital role in neurological diseases, but its detailed function in CH after SAH remains unclear
The SDS-PAGE results showed (Additional file 1: Fig. S1) that protein patterns from two non-CH controls were unreliable, at which point only the remaining three groups were used for subsequent analysis

Summary

Introduction

Communicating hydrocephalus (CH), a common neurological disorder, is associated with cognitive decline and severe deterioration of the quality of life of patients. Its combination with mechanistic experiments allows effective exploration of the potential functions of KLK proteins. Kryza et al identified the involvement of KLK14 in the aggressive characteristics of prostate cancer using a method called cell-secreted proteomics [6]. In-depth proteomic and biochemical studies on cervical–vaginal fluid demonstrated that KLK was involved in the regulation of the female reproductive system [7]. There have been no studies on the application of proteomics to study KLK6-related functions in CH. A previous study showed that KLK6 is expressed in aneurysmal SAH and as a serum prognostic biomarker [9]. Communicating hydrocephalus (CH) is a common neurological disorder caused by a blockage of cerebrospinal fluid. We aimed to explore the potential molecular mechanism underlying CH development

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