Involvement of Kallikrein-Related Peptidases in Nervous System Disorders.

Cinthia Mella,Pamela Ehrenfeld,Carlos D Figueroa,Carola Otth

doi:10.3389/fncel.2020.00166

Cinthia Mella, Pamela Ehrenfeld + Show 2 more

Open Access

https://doi.org/10.3389/fncel.2020.00166

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Abstract

Kallikrein-related peptidases (KLKs) are a family of serine proteases that when dysregulated may contribute to neuroinflammation and neurodegeneration. In the present review article, we describe what is known about their physiological and pathological roles with an emphasis on KLK6 and KLK8, two KLKs that are highly expressed in the adult central nervous system (CNS). Altered expression and activity of KLK6 have been linked to brain physiology and the development of multiple sclerosis. On the other hand, altered levels of KLK6 in the brain and serum of people affected by Alzheimer’s disease and Parkinson’s disease have been documented, pointing out to its function in amyloid metabolism and development of synucleinopathies. People who have structural genetic variants of KLK8 can suffer mental illnesses such as intellectual and learning disabilities, seizures, and autism. Increased expression of KLK8 has also been implicated in schizophrenia, bipolar disorder, and depression. Also, we discuss the possible link that exists between KLKs activity and certain viral infections that can affect the nervous system. Although little is known about the exact mechanisms that mediate KLKs function and their participation in neuroinflammatory and neurodegenerative disorders will open a new field to develop novel therapies to modulate their levels and/or activity and their harmful effects on the CNS.

Highlights

The kallikrein-related peptidases are a family of trypsin- and chymotrypsin-like serine proteases, which have significant differences regarding their amino acid sequence, relative molecular mass, substrate specificity and biochemical and functional properties (Diamandis and Yousef, 2001; Yousef and Diamandis, 2001; Stefanini et al, 2015)
In the present review article, we examine the current knowledge on the pathological implications and normal functions of human KLKs in the central nervous system (CNS) with special emphasis
Pampalakis et al (2017) have identified pro-MMP2 as a protease-activated by KLK6 that cleaves α-synuclein to produce potential fragments for the cell to cell propagation in Parkinson’s disease. These findings suggest that KLK6 is an important protease implicated in different CNS disorders in which its expression is altered in a disease-dependent manner, indicating that KLK6 may be an important therapeutic candidate to be used to ameliorate some of the effects produced by multiple sclerosis or Parkinson’s disease

Summary

Introduction

The kallikrein-related peptidases are a family of trypsin- and chymotrypsin-like serine proteases, which have significant differences regarding their amino acid sequence, relative molecular mass, substrate specificity and biochemical and functional properties (Diamandis and Yousef, 2001; Yousef and Diamandis, 2001; Stefanini et al, 2015). KLK6, Kallikrein-related peptidase 6; IHC, Immunohistochemistry; RT-qPCR, Quantitative reverse transcription Polymerase Chain Reaction; ELISA, Enzyme-linked immunosorbent assay; CNS, Central nervous system; KO, knockout; CSF, Cerebrospinal fluid; PAR, Protease-activated receptor; AD, Alzheimer’s disease; MS, Multiple Sclerosis; PD, Parkinson’s disease.

Results

Conclusion