Introduction

Furin is the first proprotein convertase (PC) found in mammals in 1990 [1]. It catalyzes the proteolytic maturation of large numbers of prohormones and proproteins in the secretory pathway compartments [1,2,3]. The substrates of furin include hormones, cytokines, growth factors and enzymes, which play important roles in cell proliferation, anti-apoptosis, immunity and inflammation [1]. Furin also participates in the proteolytic processing of proteins in viruses and bacteria [4], such as the maturation of SARS-CoV-2 spike protein [5,6,7]. Thus, aberrant activity of furin has been found to be associated with a strikingly diverse range of pathological events, including cancer, cardiovascular disorders, infectious diseases and neurological diseases [4, 8,9,10]. Among these disorders, the role of furin in neurological diseases is the most poorly understood.

In the brain, the proprotein substrates cleaved by furin in vivo include precursors of growth factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) [11, 12], α- and β-secretases [13, 14], multiple matrix metalloproteases (MMPs) [15, 16], and other enzymes and receptors [1, 17, 18]. Since these substrates play vital roles in neuronal survival, axon growth, dendritic development, synaptogenesis, neurodegeneration and inflammation [19,20,21,22], a stable activity of furin is crucial for maintaining the homeostasis of the central nervous system.

A growing body of evidence has suggested that alterations of furin expression and abnormal cleavage of its substrates contribute to the pathophysiological mechanisms of neurodegenerative and neuropsychiatric diseases. Reduced expression of FURIN mRNA has been found in the brains of Alzheimer’s disease (AD) patients [13], and decreased protein levels of furin are found in the cortex of AD mice [23]. The FURIN mRNA expression is decreased in the prefrontal cortex of schizophrenia (SCZ) patients [24], whereas increased protein levels of furin are found in the temporal cortex of epilepsy patients [25]. Moreover, studies have also shown that increasing furin expression in the mouse brain enhances BDNF maturation and promotes dendritic spine density and memory in transgenic mice [26], and that inhibiting furin expression reduces the spontaneous rhythmic electrical activity of cerebral neurons and suppresses epileptic seizure activity in epileptic mice [25]. These findings indicate the involvement of furin dysregulation in these neurological disorders, leading to increased interest in furin as a potential biomarker for diagnosis of or as a therapeutic target for treatment of neurological disorders.

In this review, we present an overview on the physiological roles of furin in the brain and deregulations of furin expression and its substrates in neurodegenerative and neuropsychiatric disorders, such as AD, Parkinson’s disease (PD), epilepsy, cerebral ischemia, SCZ and depression. We further discuss the implications of these findings and current approaches that target furin for therapeutic interventions.

Overview of furin

Gene structure and transcription of FURIN

Furin was identified in 1990 as the first mammalian PC that catalyzes the proteolytic maturation of prohormones and proproteins of neurotrophic factors, receptors and enzymes, serum proteins and pathogen molecules [1,2,3]. The human FURIN gene is located at chromosome 15q26.1, an open reading frame upstream of the fes/fps proto-oncogene [27]. It has attracted more attention after being discovered as the first mammalian homologue of yeast Kex2 [4, 28, 29]. As shown in Fig. 1a, the human FURIN gene consists of 16 exons and encodes eight different transcript variants driven by three known promoters, P1, P1A and P1B [30, 31]. The respective transcripts differ only in the first untranslated exon and therefore generate identical furin precursor proteins [30, 32]. While the P1A and P1B promoters resemble those of constitutively expressed housekee** genes, the P1 promoter is predicted to bind to many different transcription factors, including hypoxia-inducible factor-1 (HIF-1), C/EBPβ, and CREB (cAMP-responsive element binding protein) [33,34,35,36].

Fig. 1
figure 1

Human FURIN gene and furin protein structures. a The human FURIN gene consists of 16 exons and encodes eight different transcript variants driven by three known promoters, P1, P1A and P1B. Exons are shown as green boxes and introns are shown as lines. The red boxes indicate the three promoter regions. The blue arrows indicate the positions where different transcripts start. The red arrow indicates the translational start, and the start codon (ATG) and stop codon (TGA) are marked with dotted lines. b Furin protein contains an N-terminal signal peptide, a prodomain, a subtilisin-like catalytic domain, a middle P-domain, a cysteine-rich region, a transmembrane helix domain and a C-terminal cytoplasmic domain

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Several intracellular and extracellular factors have been reported to regulate FURIN expression at the transcriptional level. Hypoxia remarkably increases the expression of FURIN mRNA via stabilizing HIF-1 and enhancing its binding to hypoxia-responsive element site at the P1 promoter [37]. Iron deficiency also upregulates FURIN transcription  through stabilization of HIF-1α [35], whereas iron overload inhibits furin expression in a non-HIF-1α-dependent manner [35]. Transforming growth factor beta1 (TGFβ1) can induce transactivation of the FURIN P1 promoter through binding to Sma- and Mad-related protein 2 (SMAD2) and SMAD4 in complex with other DNA-binding partners, creating a constitutive activation/regulation positive feedback loop between TGFβ1 and furin [38]. Furthermore, extracellular regulated protein kinase 1 has been found to mediate the TGFβ–furin feedback loop in glioma-initiating cells [39]. In addition, bone morphogenetic protein 2 increases the transcription and translation of furin in human granulosa lutein cells by the activin receptor-like kinase (ALK)2/ALK3-SMAD4 signaling pathway [40].

Protein structure and expression of furin

Furin is a type I transmembrane protein and belongs to the subtilisin-like convertase family [1]. It is a calcium-dependent endoserine protease [8]. Furin protein is composed of a signal peptide, a prodomain, a subtilisin-like catalytic domain, a middle P-domain, a cysteine-rich region, a transmembrane helix domain and a cytoplasmic domain (Fig. 1b) [41]. The large extracellular region of furin has an overall homology with the same region of other members of the PC family [1]. The signal peptide directs translocation of the ~ 104-kDa pro-enzyme into the endoplasmic reticulum (ER), where the first cleavage in the inhibitory prodomain takes place via autocatalytic cleavage by the catalytic domain [42,43,44]. The second cut in the prodomain is made during trafficking of the propeptide-furin complex within the mildly acidic trans-Golgi network/endosomal system, which yields the active ~ 81-kDa mature enzyme. Furin circulates between the trans-Golgi network, cell surface and endosomes, in a tightly regulated manner, to catalyze various proproteins in different cellular components [43, 45, 46].

Furin is ubiquitously expressed in vertebrates and many invertebrates [9, 47, 48]. However, its mRNA and protein levels vary depending on the tissue and cell type [49,50,51,52,53]. FURIN has been found at high mRNA levels in the salivary gland, placenta, liver and bone marrow, and high protein levels in the brain, salivary gland, pancreas, kidney and placenta [49,50,51,52,53]. However, almost no expression is detected in skin, muscle and adipose tissues [49, 50], although substrates of furin have been identified in human adipose tissues [54]. In normal single cells, high expression of FURIN mRNA is identified in hepatocytes, exocrine glandular cells, pancreatic endocrine cells and syncytiotrophoblasts [50, 53]. This tissue- and cell-specific expression pattern of furin infers the different functions of furin in different tissues and organ systems.

Function of furin

Furin cleaves proproteins at the consensus site of Arg–X–Lys/Arg–Arg or Arg–X–X–Arg (X refers to any amino acid) [55, 56], and the cut is positioned after the carboxyl-terminal Arg residue [56]. The substrates cleaved by furin include a variety of precursor proteins within the secretory pathway, including hormones, growth factors and their receptors, neuropeptides, enzymes, adhesion molecules, metalloproteinases, bacterial toxins and viral glycoproteins [8, 29, 33]. As these molecules participate in many important cellular events, mouse embryos lacking Furin will die between days 10.5 and 11.5, with notable defects in ventral closure and axial rotation [57]. Deregulations of furin expression are found in diverse pathological conditions, including cancer, diabetes, cardiovascular disorders, inflammation and neurological diseases [10, 58,123], and is upregulated in many pathological conditions, inducing neuroinflammation and apoptosis [124]. MMP-9 is specifically shown to regulate synaptic plasticity in the hippocampus by gain- and loss-of-function studies in vitro [125, 126]. Altered concentrations of MMP-3 and MMP-9 have been found in AD patients, indicating their involvement in AD pathophysiology [127]. MMP-1, MMP-2, MMP-9 and MMP-14 can cleave recombinant α-synuclein [128, 129]. Elevated levels of MMP-2 and MMP-3 have been identified in dopaminergic (DA) neurons in the substantia nigra in PD patients and animal models [129,130,131].

ADAM10

ADAMs are another major family of zinc-dependent metalloproteases involved in limited proteolysis and shedding [132]. In the brain, ADAM10 is mainly expressed in neurons [133], and is involved in the proteolytic processing of a variety of cell surface receptors and signaling molecules [134]. ADAM10 is synthesized in the ER as an inactive zymogen with a structure comprising a prodomain, a zinc-binding metalloprotease domain, a disintegrin domain, a cysteine-rich domain, a transmembrane domain and a C-terminal domain [133]. Furin cleaves the ~ 90 kDa pro-ADAM10, yielding a full-length active ADAM10 (∼65 kDa) [135], and after C-terminal shedding, a soluble ∼55-kDa ADAM10 is released [136]. ADAM10 has α-secretase activity [137]. It cleaves amyloid-β precursor protein (APP) to generate the soluble αAPP fragment (sAPPα) rather than the neurotoxic amyloid-β (Aβ), playing a protective role in AD [138].

BACE1

BACE1 is the major β-secretase that cleaves APP to generate Aβ [139]. BACE1 is a transmembrane aspartic protease, structurally similar to the pepsin family [140], containing two active catalytic site motifs in the luminal domain [141]. Like other aspartic proteases, BACE1 is synthesized as a precursor protein containing a N-terminal propeptide domain that is removed during maturation of the enzyme [142]. Furin or a furin-like PC is responsible for cleaving the BACE1 proprotein to yield the mature enzyme with the highest β-secretase activity [143]. Like APP, BACE1 is highly expressed in the brain [144]. Significant increases of BACE1 enzymatic activity and protein concentration have been detected in brain tissues, cerebrospinal fluid (CSF) and serum of AD patients and subjects with mild cognitive impairment [145,146,147]. BACE1 inhibitors have demonstrated therapeutic effects in preventing the initial cleaving events of APP in AD animal models [148,149,150,151,152,153].

Notch receptor

The Notch gene family encodes transmembrane receptors of ~ 300 kDa that are involved in cell-fate determination in vertebrates and invertebrates [154, 155]. The proteolytic processing of Notch receptor precursor is an essential step in the formation of biologically active Notch receptors. The constitutive processing of murine Notch1 requires a furin-like convertase, and mutations in the furin-cleavage site completely abolishes the proteolysis of the Notch1 receptor [155]. In the develo** brain, activation of Notch receptors upon ligand binding is involved in the preservation of neural progenitors and inhibition of neurogenesis [156, 157]. In the adult brain, Notch signaling influences neuronal apoptosis, microglial activation and synaptic plasticity [158,159,160,161]. Deregulations of Notch signaling are involved in AD, depression, epilepsy, and stroke [159,160,161,162,163].

LRP1

LRP1 is a multifunctional receptor that belongs to the low-density lipoprotein receptor family [164]. It is synthesized as a ~ 600-kDa precursor, which is cleaved by furin in the trans-Golgi network and transported to the cell surface as a mature form consisting of α-chain and β-chain [8]. The mature LRP1 is further processed by other enzymes, such as MMPs and γ-secretase, to release the intracellular domain (ICD) [8]. LRP1 is highly expressed in neurons and glia of the brain, and functions to regulate proteinase activity, cytokine activity and cholesterol metabolism [165, 166]. The ligands for LRP1 include Aβ, ApoE and activated α2-macroglobulin [167]. In addition to controlling ligand metabolism, LRP1 can also regulate signaling pathways by coupling with other cell surface receptors or proteins, such as the N-methyl-D-aspartate (NMDA) receptors [168, 169]. The ICD of LRP1 can be transported into the nucleus, where it contributes to transcriptional regulation of target genes, including interferon-γ [170]. Accumulating evidence from preclinical and animal studies indicates that LRP1 is involved in AD pathogenesis not only by regulating the metabolisms of Aβ and ApoE, but also by influencing synaptic plasticity and inflammation through Aβ-independent pathways [171]. LRP1 is detected at an abundant level in post-synaptic sites of neurons, and it interacts with several synaptic proteins, including postsynaptic density protein 95, NMDA receptor and GluA1 [169, 171,172,173]. Deletion of LRP1 in neurons has been shown to affect lipid metabolism, leptin signaling, glucose metabolism, insulin signaling and anti-apoptotic signaling, resulting in neuroinflammation, motor dysfunction, and cognitive decline in mice [171, 172, 174, 175]. In addition, LRP1 is also found to modulate stem cell proliferation and survival, astroglial differentiation [176, 177], and oligodendrocyte progenitor cell differentiation [178].

GPR37

GPR37 is an orphan G-protein-coupled receptor that is widespread in several brain regions, including cerebral cortex, hippocampus, hypothalamus, midbrain and cerebellum [51]. It has a long extracellular N-terminal ectodomain which is recently demonstrated to be processed by both ADAM10 and furin [179]. The unfolded form of GPR37 is a substrate of parkin, and its intracellular retention leads to ER stress and DA neuronal death, linking to PD [180,181,182]. GPR37 is also involved in the DA signaling pathway by interacting with the dopamine transporter in mouse striatal presynaptic membranes, thereby modulating dopamine uptake [183]. In addition, GPR37 interacts with adenosine A2A receptors in the hippocampus, localized at the extrasynaptic plasma membrane of dendritic spines, dendritic shafts and axon terminals, regulating adenosinergic signaling [184]. GPR37 is also found in astrocytes and oligodendrocytes, and is demonstrated as a negative regulator of oligodendrocyte differentiation and myelination [185, 186]. Overexpression of GPR37 leads to profound neurodegeneration in animal models, selectively for DA neurons [187], while GPR37-knockout mice also show decreased dopamine levels in the striatum and specific motor deficits [188, 189]. GPR37 knockout also triggers non-motor behavioral phenotypes, such as anxiety and depression-like behaviors, in an age- and gender-dependent manner [190, 191].

Sortilin

Sortilin is a type I transmembrane protein that functions as an endocytosis receptor and plays a role in protein sorting and cell signaling [192]. Sortilin is synthesized as an inactive precursor protein, which is cleaved by furin to remove the N-terminal propeptide [193]. The resulting mature protein can be further processed by other proteases to shed its extracellular domain from the cell surface [193]. Sortilin is generally trafficked via the trans-Golgi network, endosomes and plasma membrane, binding to different proteins and directing them to the secretory pathway or for degradation [193]. Sortilin has been reported to function as a neuronal receptor for APP and its cleavage products sAPPα and Aβ [194, 195]. The ICD of sortilin interacts with APP and regulates its lysosomal and lipid raft trafficking [194]. Sortilin also binds to oligomerized Aβ, inducing endocytosis of Aβ and triggering apoptosis [195]. In addition, sortilin is found to be an essential component for transmitting pro-neurotrophin-dependent death signals from p75NTR, thereby playing roles in neuronal apoptosis, aging and brain injury [93, 196, 197]. On the other hand, sortilin has also been found to associate with TrkB receptors, which promotes cell survival [198]. Therefore, sortilin acts as a molecular switch from apoptotic response by interacting with p75NTR to neurotrophic effects via binding to TrkB receptors in neurons. Aberrant activity of sortilin has been found to be associated with the pathogenesis of AD and depression [193, 199, 200].

BRI2

BRI2 is a type II transmembrane protein of 266 amino acids, containing an extracellular region, a transmembrane region and a cytoplasmic region [201, 202]. During maturation, the ~ 4-kDa C-terminal propeptide of BRI2 is cleaved by furin at the trans-Golgi compartment, generating the membrane-bound form of mature BRI2 (mBRI2) [203, 204]. The mBRI2 contains an evolutionarily conserved BRICHOS domain that is found to act as a chaperone, facilitating proper folding of BRI2 and preventing Aβ formation [205, 206]. In the human brain, BRI2 is intensively expressed in cortical and hippocampal pyramidal neurons [207]. The BRICHOS domain of BRI2 interacts with APP and inhibits its processing, delaying fibrillation of Aβ [206,207,208,209]. Mutations in BRI2 and aberrant BRI2 expression have been reported to be associated with familial British dementia and involved in AD pathogenesis [210,211,212].

Ac45

Ac45, an accessory subunit of the vacuolar-type ATPase (V-ATPase) proton pump, is a type I transmembrane protein that is encoded by ATP6AP1 in humans [213,214,290].

Potential role of furin in the pathology of epilepsy

The above findings suggest a crucial role of furin in the pathology of epilepsy. The upregulation of furin in epilepsy patients or animal models may promote the cleavage of proBDNF, proNGF, Notch receptor and MMPs. As a result, the inhibitory and excitatory synaptic transmissions are affected, leading to abnormal neuronal discharge, which contributes in part to the symptoms of epilepsy (Fig. 3b). However, the underlying mechanisms for furin upregulation and furin-mediated activities in epileptogenesis need to be determined.

Furin in cerebral ischemia

Overview of cerebral ischemia

Cerebral ischemia is a neurodegenerative disease caused by reduced blood supply to the brain tissue [291], and is currently a major cause of death and disability globally [292]. Cerebral ischemia causes reduced delivery of oxygen and glucose to the brain, and as a result, a loss of consciousness can occur [291]. The occurrence of metabolic disorders during ischemia or tissue hypoxia is relatively well established, but the subsequent reperfusion is the major events leading to cell and tissue dysfunctions [293]. Ischemia–reperfusion injury is the inexplicable aggravation of cellular dysfunction during the restoration of blood flow after a period of ischemia [294]. The reperfusion can lead to potentially very harmful effects, such as necrosis of irreversibly damaged cells, cell swelling, vascular and endothelial injury and mitochondrial dysfunction [295].

Aberrant furin expression in cerebral ischemia

It has been found that the Furin mRNA level in rat hippocampus at 24 h after transient global cerebral ischemia is two-fold of that in sham-operated controls, indicating a possible role furin may play [296]. In a focal ischemic rat model established by middle cerebral artery occlusion, increases in Furin mRNA and protein levels are found in the piriform cortex of the ischemic hemisphere 2 h after reperfusion compared with sham-operated animals, and it is predicted that the elevation of furin may contribute to the disruption of BBB during ischemia [297]. Another recent study found that the level of Furin mRNA in the ipsilateral cortex of hypoxic-ischemic rats had an insignificant increase at 6 h after ischemia, but then decreased significantly at 15 h and was sustained at a low level for 7 days [298], while Furin mRNA in the ipsilateral hippocampus was elevated at 6 h and 3 days but decreased at 15 and 24 h after injury compared with that of the control rats [298]. The change in furin expression is considered to account for the decrease of BDNF in the ipsilateral cortex and hippocampus of the rats [298]. An in vitro study also showed that the protein levels of furin and BDNF are upregulated in cultured rat astrocytes exposed to oxygen–glucose deprivation [64]. These findings indicate that furin may play important roles in the pathogenesis of cerebral ischemia and in the recovery from ischemia brain damage.

Expression of substrates of furin in cerebral ischemia

In addition to the changes in furin expression, the levels of Bdnf mRNA and protein in the ipsilateral cortex and hippocampus of hypoxic-ischemic rats are altered at different degrees at different time points after hypoxic-ischemic injury [298]. Many other studies have also reported changes of MMP levels, including levels of MMP-2, MMP-9 and MMP-14, in the model of focal ischemic rats [297, 299,300,301,302]. In particular, increased expression and activity of MMP-2 and MMP-9 are found in different models of focal cerebral ischemia, implying their potential roles in early matrix degradation, loss of vascular integrity, and neuronal injury in the ischemic lesion [300, 301]. In addition, a significant increase in the cleavage of LRP1 by furin has been found in rats after cerebral ischemia, which is predicted to aggravate neuroinflammation, and administration of a furin inhibitor inhibits the cleavage of LRP1 and decreases co-localization of ICD of LRP1 with furin in ischemic areas [303]. These findings imply that the furin-mediated cleavage of MMPs and LRP1 may be involved in the pathophysiology of ischemic brain injury.

Potential role of furin in the pathology of ischemia

The above observations imply the involvement of furin in the pathology of cerebral ischemia. Changes in furin expression may exist in varied temporal and spatial patterns after ischemic injury in the brain. The upregulation of furin in ischemic patients or animal models may promote the cleavage of MMPs, particularly MMP-2, MMP-9, and MMP-14. The activation of these MMPs leads to early matrix degradation and loss of vascular integrity, and finally contributes to BBB breakdown and neuronal injury in ischemic lesions (Fig. 3c). Moreover, the ICD of LRP1 is increased, which aggravates neuroinflammation. The relationship between changes of furin level and other molecules such as BDNF in ischemic brain injury needs to be elucidated in the future.

Furin in SCZ

SCZ overview

As one of the severe mental diseases, schizophrenia is characterized by cognitive distortions including impairments in concentration, thinking, speed of cognitive information processing, and verbal working memory [304]. These impairments in cognitive functions persist throughout the disease and determine the functional status of patients [305]. The etiology of schizophrenia is complex, commonly associated with genetic variants and changes in development-related factors and regulatory molecules [306].

Aberrant furin expression in SCZ

A study by Fromer et al. in 2016 using RNA sequencing data from the dorsolateral prefrontal cortex of post-mortem SCZ patients identified down-regulation of FURIN transcripts by risk allele [24]. They also found that depletion of furin in zebrafish model has the largest impact on head size, which can be attributed to the furin depletion-induced changes in neural cell proliferation and migration [24]. Furthermore, downregulation of furin expression specifically at the rs4702 G (in the 3' UTR of FURIN) allele by miR-338-3p reduces the production of mBDNF [307]. In addition, the association between pleiotropic effects of FURIN genetic loci and SCZ traits has been reported recently by several different studies [308,309,310]. A study using datasets from the Psychiatric Genomics Consortium related to SCZ, major depressive disorder (MDD) and bipolar disorder (BIP) patients identified rs8039305 in the FURIN gene as a novel pleiotropic locus across the three disorders [309]. Similarly, another study identified rs17514846, a variant within an intron of FURIN gene, as a common trait between SCZ and cardiometabolic disorder [310]. In addition, in C. elegans, the 3'UTR of kpc-1 (furin) promotes dendritic transport and local translation of mRNAs to regulate dendrite branching and self-avoidance [311]. These findings indicate the important role of furin in brain development and in the pathophysiology of SCZ.

Expression of substrates of furin in SCZ

The deregulation of BDNF expression has been extensively studied in SCZ patients and animal models [312,313,314,315,316,317,318,319]. Significant reductions of BDNF mRNA and protein have been observed in the dorsolateral prefrontal cortex of patients with SCZ compared to normal individuals [312]. The reduced BDNF/TrkB signaling in the prefrontal cortex appears to underlie the dysfunctions of inhibitory neurons in subjects with SCZ [313]. Studies have also shown significant reductions of BDNF in the hippocampus as well as NT-3 concentrations in the frontal and parietal cortical areas, in SCZ patients [314]. On the contrary, some studies have shown that the BDNF concentration is significantly increased in cortical areas of post-mortem SCZ patients [314, 315]. In addition, the plasma BDNF levels in schizophrenic patients are remarkably lower than those in the controls, which is predicted to be associated with the decreased hippocampal volume and cognitive impairments in first-episode and chronic SCZ [316, 317]. These findings suggest that the downregulation of neurotrophic factors could be responsible for neural maldevelopment and disturbed neural plasticity in the etiopathogenesis of schizophrenic psychoses. In schizophrenic animal models, reductions of Bdnf mRNA and protein levels have been observed in the cortex and the hippocampus [318, 319]. Decreased serum levels of NGF and NT-3 have been observed in SCZ as well [320,321,322]. In addition to the alterations of neurotrophins, plasma MMP-9 levels are also increased significantly in SCZ patients compared to controls [323], and MMP-9 gene polymorphisms in the brain are found to be associated with SCZ [324, 325]. Besides, increased MMP-2 levels in the CSF of SCZ patients are also reported [326].

Potential role of furin in SCZ pathology

The above findings uncover the involvement of furin in the pathology of SCZ. Furin expression in SCZ patients is downregulated, which in turn affects the maturation of neurotrophins, such as BDNF, NGF and NT3. The chronic low trophic support for neurons leads to neural maldevelopment, dysfunction of inhibitory neurons, disturbed neural plasticity and neurodegeneration, contributing to the impaired cognitive performance/function in SCZ (Fig. 3d). This hypothesis may in part explain the pathogenesis of SCZ. However, the relationships between furin deregulation and changes in MMPs and other furin substrates in SCZ pathology have yet to be investigated.

Furin in depression and anxiety

Currently, there is no report on the changes of furin expression in patients with depression and anxiety. However, the SNP rs8039305 in the FURIN gene has been indicated as a novel pleiotropic locus across the disorders of MDD, BIP and SCZ [309], indicating a potential role of furin in pathological mechanisms of the psychiatric disorders.

Aberrant expression of several substrates of furin has been reported in patients with depression. The serum BDNF level is significantly lower in MMD patients than in healthy controls [327,328,329]. The mBDNF/proBDNF ratio is also decreased [329], suggesting that the reduced BDNF maturation plays a pivotal role in the pathophysiology of MDD. Serum MMP-9 is found to be increased in MDD patients, while MMP-2 is decreased in MDD patients [323, 330], indicating the involvement of MMP-2 and MMP-9 in mood disorders. In addition, MMP-2 levels in the CSF are increased in MDD patients [326], and the state-dependent alterations of MMP-2 and activation of cascades involving MMP-2, MMP-7, and MMP-10 appear to play a role in the pathophysiology of MDD [326]. LRP1 has been reported to be up-regulated in the hippocampus of depressive-like rat model [331].

In anxiety-like disorders, aberrant BDNF expression has also been reported. In the social deprivation stress-triggered anxiety- and depressive-like mice, BDNF levels are reduced in the brain [332]. In serotonin transporter knockout rats with depressive- and anxiety-like behavior, a decrease in mBDNF in the prefrontal cortex has been reported as well [333]. The alterations of proBDNF and mBDNF expression have been indicated in many other diseases with anxiety- and depressive-like behavior [334,335,336,337], highlighting the association between aberrant BDNF expression and anxiety and depression disorders.

Furin-targeting strategies for neurological diseases

Currently, the use of furin-targeting strategies to diagnose or treat neurological disorders has not been reported in clinical studies. However, as described above, furin expression levels are altered in several neurodegenerative and neuropsychiatric diseases; for instance, serum furin level is decreased in AD mice. These highlight the great potential of furin to be a predictive diagnostic marker for neurological disorders in the future.

The potentials of furin-targeting strategies to treat neurological diseases have been suggested in several animal models (Table 2). In AD animal models, injection of Furin-adenovirus into the cortex of Tg2576 mice markedly increases the α-secretase activity of ADAM10 and TACE, which in turn reduces Aβ production [13]. Furin-transgenic mice with brain-specific overexpression of furin exhibit increased dendritic spine density and enhanced learning and memory, which are attributed to the increased mBDNF level caused by furin [26]. In aged APP-C105 mice, treadmill exercise attenuates AD-related symptoms, possibly by ameliorating iron dyshomeostasis and enhancing furin expression, thereby promoting α-secretase-directed processing of APP [23]. Gallic acid treatment in APP/PS1 mice has been shown to increase furin expression, which in turn promotes α-secretase activity and decreases Aβ production, partly reversing the learning and memory impairment in APP/PS1 mice [338]. In addition, cerebrolysin, a peptidergic mixture with neurotrophic-like properties, can improve the survival of neural stem cell grafts and alleviate Aβ deposition in the hippocampus of APP transgenic mice, and this protective effect also involves the activation of furin and increased BDNF expression [339]. On the other hand, knockdown of astrocytic Grin2a in rats reduces furin expression and in turn decreases the maturation and secretion of NGF, aggravating the Aβ-induced memory and cognitive deficits [238]. These findings suggest the potential of increasing furin expression as an effective approach for AD treatment, and open avenues for future targets and strategies for AD prevention and therapeutic interventions.

Table 2 Treatment effects of modulation of furin expression on neurological diseases
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In paraquat-induced Drosophila model of PD, transgenic knockdown of Fur1 in DA neurons provides significant protection against the loss of DA neurons [265]. In Drosophila models with LRRK2 overexpression, disruption of one allele of Fur1 or postsynaptic knockdown of Fur1 using transgenic RNA interference approach can attenuate the LRRK2-induced retrograde synaptic enhancement [266]. These findings suggest potential involvement of furin in PD pathophysiology and treatment. However, great efforts are urgently needed to explore the role and pharmaceutical potential of furin in PD patients or murine models.

In both KA-induced and PTZ-kindled epileptic mouse models, lentivirus-mediated knockdown of furin in the hippocampus decreases the spontaneous rhythmic electrical activity of cerebral neurons, and suppresses epileptic seizure activity and severity [25]. This protective role is proposed to be associated with the regulation of synaptic transmission by altering the transcription level of postsynaptic gamma-amino butyric acid A receptor [25].

In a global ischemia/reperfusion rat model, monosialoganglioside or flavanol epicatechin treatment both can improve spatial memory retention and acquisition in experimental ischemic rats [340], and these neurotherapeutic effects are found to be related to the increases in furin and NGF levels [340]. In addition, application of furin inhibitor can protect primary cortical neurons from cell death induced by activated NMDA receptors [341], which is possibly attributed to the decrease of furin-mediated cleavage of LRP1 [303]. These findings suggest that manipulating furin expression is potentially a good strategy for the treatment of ischemic brain injury.

In addition, some furin activators and inhibitors have been identified with drug potentials. The small molecules phorbol esters dPPA (12-deoxyphorbol 13-phenylacetate 20-acetate) and dPA (12-deoxyphorbol 13-acetate) exhibit great effects in promoting furin expression via activation of the transcription factor CEBPβ in neuronal cells [34]. On the other hand, polyarginines, such as hexa-D-arginine, significantly inhibit furin activity in vivo [342, 343]. The therapeutic effects of these furin activators and inhibitors in prevention and treatment of neurological disorders need to be investigated further in the future.

Conclusions

A growing body of evidence has suggested the crucial role of furin in the pathophysiological conditions of neurodegenerative and neuropsychiatric diseases. Notably, reduced furin expression is closely associated with the pathogenesis of AD. Pharmaceutical targeting of furin expression has shown great promise for AD treatment. In addition to AD, alterations of furin expression also exist in patients or animal models of epilepsy, cerebral ischemia, or SCZ. Furthermore, changes in the expression of neurotrophins, such as BDNF and NGF, are common to these neurodegenerative and neuropsychiatric diseases, and many are related to the abnormal cleavage of proneurotrophins. In addition to neurotrophins, other substrates of furin such as MMPs and LRP1 also exhibit expression changes in these neurodegenerative and neuropsychiatric diseases. These lines of evidence highlight the important roles of furin and furin-mediated activities in the progression of these diseases, and render furin as a valuable therapeutic target. However, currently very little is known about the cellular and molecular mechanisms of furin regulation in these diseases. Future studies are needed to clarify the molecular mechanisms of furin deregulation and its involvement in the pathogenesis of these diseases, and to develop new diagnostic and treatment strategies.