Table 1 Changes in the expression of furin and its substrates in neurodegenerative and neuropsychiatric diseases and the implications
From: The emerging role of furin in neurodegenerative and neuropsychiatric diseases
Disease | Patients/animal models | Furin expression | Expression of proteins processed by furin | Implications | References |
|---|---|---|---|---|---|
AD | AD patients | FURIN mRNA (brain) ↓ |  | Furin reduction may be closely related to the mechanisms that lead to Aβ production in AD | [13] |
AD | Tg2576 mice | Furin mRNA (cortex) ↓ |  | Furin reduction downregulates α-secretase activity of ADAM10 and TACE, thereby enhancing Aβ production | [13] |
AD | APP-C105 mice | Furin (cortex) ↓ | ADAM10 (cortex) ↓ | Excess iron induces disruption of furin activity, which in turn reduces α-secretase-dependent APP processing | [23] |
AD | AD patients | Furin (plasma) ↓ |  | Increased plasma iron concentration in AD downregulates furin level, impairing the ability of α-secretases to produce sAPPα, resulting in increased Aβ | [237] |
AD | AD patients |  | BDNF mRNA (hippocampus) ↓; BDNF (hippocampus) ↓ | Deficiency of BDNF may contribute to the progressive atrophy of neurons in AD | |
AD | AD patients |  | BDNF mRNA (cortex) ↓; mBDNF (cortex) ↓; mBDNF/proBDNF (cortex) ↓ | Imbalanced proBDNF and mBDNF play a role in synaptic loss and cellular dysfunction, leading to cognitive impairment in AD | |
AD | Tg2576 mice |  | mBDNF (hippocampus) ↓; mBDNF/proBDNF (hippocampus) ↓ | Abnormal cleavage of BDNF may be involved in AD-related traits triggered by excessive Aβ pathology | [247] |
AD | 5 × FAD mice |  | BDNF (hippocampus) ↓ | BDNF expression is reduced in 5 × FAD mice at the age of 3 and 7 months, contributing to the impairment of synaptic plasticity and memory | |
AD | AD patients |  | proNGF (cortex) ↑ | Decreased processing of proNGF to mNGF may be associated with AD pathology | |
AD | AD patients |  | proNGF (hippocampus) ↑ | Alterations in the hippocampal NGF signaling pathway in AD favor proNGF-mediated proapoptotic pathways | [251] |
AD | AD patients |  | Notch1 (hippocampus) ↑ | Notch1 is increased in AD and Pick’s disease, where abnormal tau aggregates are present, indicating a possible relationship between tau aggregation and Notch1 expression | [252] |
AD | AD patients |  | MMP-1 (cortex) ↑ | Enhanced MMP-1 activity in AD may contribute to the BBB dysfunction seen in AD | [255] |
AD | AD patients |  | BACE1 mRNA (cortex) ↑ BACE1 (cortex) ↑ | Increased BACE1 activity is correlated with Aβ level in AD | |
AD | AD patients |  | BACE1 (CSF) ↑ | Increased BACE1 in CSF is a predictor of mild cognitive impairment | [146] |
AD |  5× FAD mice |  | MMP-2 (hippocampus) ↑; MMP-9 (hippocampus) ↑; MMP-14 (hippocampus) ↑ | Different MMPs involved in APP/Aβ metabolism are differentially regulated in a spatio-temporal manner in the  5× FAD murine model of AD | [256] |
AD | AD patients |  | Sortilin (cortex) ↑ | Sortilin functions as a modulator of BACE1 retrograde trafficking and promotes the generation of Aβ | [199] |
AD | AD patients |  | Sortilin (hippocampus) ↑; ProBDNF (hippocampus) ↑; ProBDNF/BDNF (CSF) ↑ | ProBDNF-p75/sortilin signaling is an important contributor to the pathogenesis of AD, causing an increase of cell death and impairment of neuronal differentiation | [257] |
AD | AD patients |  | LRP1 mRNA (cortex) ↑; LRP1 (brain) ↑ | LRP1 expression may be upregulated in glial cells due to the neuroinflammation in AD | |
AD | AD patients |  | LRP1 (cortex) ↓ | LRP1 pathway may modulate Aβ deposition and AD susceptibility by regulating the removal of soluble Aβ | [260] |
AD | APP23 mice |  | LRP1 (cortex) ↑; LRP1 (cortical blood vessels) ↓ | LRP1 increase in the cortex and decrease in vascular endothelial cells may account for an imbalance of Aβ efflux and influx across the BBB in AD mice | [261] |
AD | AD patients |  | BRI2-BRICHOS (hippocampus) ↑; BRI2-APP (hippocampus) ↓ | Aberrant processing of BRI2 may promote its deposition and affect its function in halting Aβ aggregation | [212] |
PD | LRRK2-overexpressing Drosophila | Furin 1 (DA neurons) ↑ |  | LRRK2 enhances furin 1 translation in DA neurons, mediating neurotoxicity in the fly model of PD | [265] |
PD | Paraquat-treated Drosophila | Furin 1 (DA neurons) ↑ |  | Furin 1 may initiate a cellular program that is central to the process of neurodegeneration | [265] |
PD | PD patients |  | BDNF (CSF) ↑ | Altered BDNF level could be involved in the pathophysiology of PD | [267] |
PD | PD patients |  | BDNF (serum) ↓ | Lower serum levels of BDNF at early stage may be associated with the pathogenesis of PD | |
PD | PD patients |  | MMP-2 (substantia nigra) ↓ | Region-specific alterations of MMPs may contribute to the pathogenesis of PD | [131] |
PD | 6-Hydroxydopamine-treated rats |  | MMP-3 (substantia nigra) ↑ | Activation of MMP-3 processes the secreted α-synuclein in PD | [129] |
PD | PD patients |  | MMP-1 (serum) ↓ | Significantly lower levels of serum MMP-1 were found in PD patients, particularly in females | [270] |
PD | PD patients |  | GPR37 (Lewy bodies in midbrain) ↑ | GPR37 may be involved in the formation of Lewy bodies, mediating neurotoxicity in PD | [181] |
PD | PD patients |  | GPR37 mRNA (substantia nigra) ↑; Ecto-GPR37 (CSF) ↑ | Ecto-GPR37 in CSF is a potential biomarker for PD | [182] |
Epilepsy | TLE patients | Furin (temporal cortex) ↑ |  | There might be a correlation between furin expression and epilepsy | [25] |
Epilepsy | KA-induced epileptic mice; PTZ-kindled epileptic mice | Furin (cortex, hippocampus) ↑ |  | Furin may play a role in regulation of inhibitory synaptic transmission in epileptic mice | [25] |
Epilepsy | KA-induced epileptic mice | Furin mRNA (hippocampus) ↑ | Ngf mRNA (hippocampus) ↑; Bdnf mRNA (hippocampus) ↑ | Furin mRNA upregulation appears to be parallel to that of NGF and BDNF mRNAs following KA treatment | [12] |
Epilepsy | TLE patients |  | BDNF/NGF/NT-3 mRNA (hippocampus) ↑ | There may be associations between increased neurotrophin mRNA levels in granule cells and damage to hippocampal neurons and synaptic plasticity in epilepsy | [276] |
Epilepsy | TLE patients |  | BDNF (temporal cortex) ↑ | The activity-dependent expression of BDNF in human subjects potentially contributes to the pathophysiology of human epilepsy | [277] |
Epilepsy | Pilocarpine-induced status epileptic mice |  | ProBDNF (hippocampus) ↑ | Rapid increases of proBDNF following epilepsy are due in part to reduced cleavage | [278] |
Epilepsy | Rats with limbic seizures induced by electrolytic lesion in DG |  | Ngf mRNA (hippocampus) ↑; Ngf mRNA (cortex) ↑ | The expression of NGF is affected by unusual physiological activity | [279] |
Epilepsy | KA-induced epileptic rats |  | Ngf mRNA (forebrain) ↑ | Seizure activity stimulates a transient increase of NGF expression by selective populations of forebrain neurons | [280] |
Epilepsy | Pilocarpine-induced status epileptic rats |  | ProNGF (hippocampus) ↑ | High levels of mRNA for both p75 receptors and proNGF are found in the epileptic model rats | [281] |
Epilepsy | TLE patients; KA-induced epileptic mice |  | Notch (hippocampus) ↑ | The effect of Notch signaling on seizures can be in part attributed to its regulation of excitatory synaptic activity in CA1 pyramidal neurons | [163] |
Epilepsy | Epilepsy patients |  | MMP-2 (serum) ↓; MMP-3 (serum) ↓ | Serum MMP-2 and MMP-3 are potential biomarkers for epilepsy | [283] |
Epilepsy | TLE patients; |  | MMP2 mRNA (hippocampus) ↑; MMP3 mRNA (hippocampus) ↑; MMP14 mRNA (hippocampus) ↑ | Increased MMP expression is a prominent hallmark of the human epileptogenic brain | [285] |
Epilepsy | Intractable epilepsy patients |  | MMP-9 (cortex) ↑ | Increased MMP-9 immunoreactivity was prominently upregulated at synapses in the cortex of intractable epilepsy patients | [286] |
Epilepsy | PTZ-induced kindled epileptic mice |  | MMP-9 (hippocampus) ↑ | MMP-9 is involved in the progression of epilepsy through cleavage of proBDNF to mBDNF in the hippocampus | [287] |
Cerebral ischemia | Global ischemic rats | Furin mRNA (hippocampus) ↑ |  | Furin may protect hippocampal neurons from ischemic damage | [296] |
Cerebral ischemia | Rats after MCAO | Furin mRNA (ischemic hemisphere) ↑ | Mmp2 mRNA (ischemic hemisphere) ↑; Mmp14 mRNA (ischemic hemisphere) ↑ | Furin activates MMP-14 and in turn enhances MMP-2 activation, contributing to the disruption of BBB in ischemia | [297] |
Cerebral ischemia | Hypoxic-ischemic rats | Furin mRNA (ipsilateral cortex) ↓; Furin mRNA (ipsilateral hippocampus) ↑ ↓ ↑ | BDNF (ipsilateral cortex, hippocampus) ↓; Mmp9 mRNA (ipsilateral cortex) ↓ | BDNF and its related enzymes such as furin play important roles in the pathogenesis of and recovery from hypoxic-ischemic brain damage | [298] |
Cerebral ischemia | Rats after MCAO |  | MMP-2 (ipsilateral cortex, striatum) ↑; MMP-9 (ipsilateral cortex, striatum) ↑ | A specific spatial–temporal pattern of expression and activation of MMP-9 and MMP-2 may contribute to extracellular matrix degradation and BBB breakdown after transient focal cerebral ischemia | [299] |
Cerebral ischemia | Baboons after MCAO |  | MMP-2 (basal ganglia) ↑ | It is plausible that locally active MMP-2 contributes to early matrix degradation, loss of vascular integrity, neuron injury, and maturation of the ischemic lesion | [300] |
Cerebral ischemia | Mice after MCAO |  | MMP-9 (ischemic regions) ↑ | MMP-9 may play an active role in early vasogenic edema development after stroke | [302] |
Cerebral ischemia | Rats after MCAO |  | LRP1-ICD (ischemic areas) ↑ | Furin-mediated cleavage of LRP1 and changes in LRP1-ICD localization are involved in ischemic brain injury | [303] |
SCZ | SCZ patients | FURIN mRNA (prefrontal cortex) ↓ |  | Aberrant gene expression elucidates the functional impact of polygenic risk for SCZ | [304] |
SCZ | SCZ patients |  | BDNF mRNA (cortex) ↓; BDNF (cortex) ↓ | Cortical neurons may receive less trophic support in SCZ | [312] |
SCZ | SCZ patients |  | BDNF mRNA (cortex) ↓ | Decreased BDNF/TrkB signaling appears to underlie the dysfunction of inhibitory neurons in SCZ | [313] |
SCZ | SCZ patients |  | BDNF (hippocampus) ↓; NT-3 (cortex) ↓ | Alterations in expression of neurotrophic factors could be responsible for neural maldevelopment and disturbed neural plasticity in SCZ | [314] |
SCZ | SCZ patients |  | BDNF (serum) ↓ | BDNF may be involved in the pathophysiology of and cognitive impairment in SCZ | |
SCZ | Rats with ibotenic acid lesions in the hippocampus |  | Bdnf mRNA (cortex) ↓; Bdnf mRNA (hippocampus) ↓ | Alterations in BDNF render animals more susceptible to neurodegenerative insults | [318] |
SCZ | Dysbindin-1 mutant mice |  | BDNF (cortex) ↓; BDNF (hippocampus) ↓ | BDNF reduction leads to inhibitory synaptic deficits | [319] |
SCZ | SCZ patients |  | NGF (serum) ↓; NT-3 (serum) ↓ | SCZ is accompanied by an abnormal neurotrophin profile | |
SCZ | SCZ patients |  | MMP-9 (serum) ↑ | Alterations in plasma MMP-9 are a biomarker for SCZ | [323] |
SCZ | SCZ patients |  | MMP-2 (CSF) ↑ | Increased CSF MMP-2 levels in SCZ may be associated with brain inflammation | [326] |
Depression | MDD patients |  | BDNF (serum) ↓ | Low BDNF levels may play a pivotal role in the pathophysiology of MDD | |
Depression | MDD patients |  | BDNF (serum) ↓; mBDNF/proBDNF (serum) ↓ | The changes in serum BDNF, TrkB, proBDNF and p75NTR may provide a diagnostic biomarker for MDD | [329] |
Depression | MDD patients |  | MMP-9 (serum) ↑; MMP-2 (serum) ↓ | MMP-2 and MMP-9 are involved in the pathophysiology of major depression | [323] |
Depression | Mood disorder patients |  | MMP-2 (serum) ↓ | A change in inflammatory homeostasis, as indicated by MMP-2 and MMP-9, could be related to mood disorders | [330] |
Depression | MDD patients |  | MMP-2 (CSF) ↑; MMP-7 (CSF) ↑; MMP-10 (CSF) ↑ | Increased MMP-2 levels in CSF are positively correlated with clinical symptomatic scores in MMD | [326] |
Depression | Rats after chronic unpredictable mild stress |  | Lrp1 mRNA (hippocampus) ↑; LRP1 (hippocampus) ↑ | LRP1 might impair the microtubule dynamics in depressive-like rats and is involved in the development of depression | [331] |