Fyn Kinase Activity and Its Role in Neurodegenerative Disease
Pathology: a Potential Universal Target?
Bianca Guglietti1
· Srisankavi Sivasankar1
· Sanam Mustafa1,2 · Frances Corrigan1
· Lyndsey E. Collins‑Praino1,2
Received: 14 May 2021 / Accepted: 3 August 2021
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021
Fyn is a non-receptor tyrosine kinase belonging to the Src family of kinases (SFKs) which has been implicated in several
integral functions throughout the central nervous system (CNS), including myelination and synaptic transmission. More
recently, Fyn dysfunction has been associated with pathological processes observed in neurodegenerative diseases, such as
multiple sclerosis (MS), Alzheimer’s disease (AD) and Parkinson’s disease (PD). Neurodegenerative diseases are amongst the
leading cause of death and disability worldwide and, due to the ageing population, prevalence is predicted to rise in the com￾ing years. Symptoms across neurodegenerative diseases are both debilitating and degenerative in nature and, concerningly,
there are currently no disease-modifying therapies to prevent their progression. As such, it is important to identify potential
new therapeutic targets. This review will outline the role of Fyn in normal/homeostatic processes, as well as degenerative/
pathological mechanisms associated with neurodegenerative diseases, such as demyelination, pathological protein aggrega￾tion, neuroinfammation and cognitive dysfunction.
Keywords Parkinson’s disease · Alzheimer’s disease · Multiple sclerosis · Therapeutic · Infammation · NMDA receptors
Neurodegenerative diseases are amongst the leading cause
of death and disability worldwide [1]. They encompass a
range of diseases associated with progressive loss of neu￾rons, the most common of which include multiple sclerosis
(MS), amyotrophic lateral sclerosis (ALS), Alzheimer’s dis￾ease (AD) and Parkinson’s disease (PD). Involving a range
of motor and cognitive impairments, neurodegenerative
diseases are both progressive and incapacitating in nature.
Due to increased life expectancy and population growth
worldwide, prevalence of these age-associated diseases is
expected to continue to rise [2]. Accordingly, these represent
a considerable burden on worldwide health-care systems
and the individuals and carers who experience them. For
example, for PD alone, counts of prevalence, mortality and
disability-adjusted life years (DALYs) more than doubled
from 1990 to 2016 [3]. Similarly, it currently accounts for
a total US economic burden of $52 billion, a fgure that
has previously been under-estimated and that is projected to
surpass $79 billion by 2037 [4].
Perhaps the greatest concern regarding the increasing
prevalence of neurodegenerative diseases are the limitations
of current therapeutic interventions. At present, there are no
available disease-modifying agents for these conditions, with
currently available treatments largely restricted to sympto￾matic relief [5]. These do nothing to halt, delay or slow the
inevitable degenerative progression of pathologies observed,
highlighting the growing need to identify novel therapeutic
targets. A potential approach may be to target common cel￾lular mechanisms underlying several of the major neuro￾degenerative diseases. Due to its diverse role in the human
central nervous system (CNS), one such promising target
may be the tyrosine kinase Fyn.
Fyn is one of eleven members of the Src family of tyros￾ine kinases (SFKs) [6]. Widely expressed in many tissues,
in recent years, Fyn has garnered signifcant attention in
cancer research due to its role in the signalling pathways
that control cell proliferation, migration, invasion and
apoptosis [7]. Excitingly, in vivo work demonstrated Src
family inhibitors, including Fyn, were able to inhibit solid
tumour growth [8]. Unfortunately, the progression to phase
II human trials in cancers, such as melanoma, breast cancer
* Lyndsey E. Collins-Praino
[email protected]
1 Department of Medical Sciences, University of Adelaide,
SG31, Helen Mayo South, Adelaide, SA 5005, Australia
2 ARC Centre of Excellence for Nanoscale BioPhotonics,
University of Adelaide, Adelaide, Australia
and pancreatic cancer, found limited beneft due to the high
threshold required for kinase inhibition in order to modify
tumour progression (>98%) [6]. Whilst this was a signif￾cant setback for Fyn as a target in oncological applications,
as research in the area of Src kinases developed, so too did
a greater understanding of the diverse role of Fyn in neu￾rological function. A recent review by Matrone and col￾leagues summarised several of the key functions of Fyn in
neurological processes, cementing its pivotal and versatile
role in the brain [9]. Indeed, Fyn plays a signifcant role in
myelination, neurodevelopment and SP, as well as modulat￾ing the neuroinfammatory response, key processes that are
disrupted in neurodegenerative disease [10–12]. This review
will critically consider how alterations in Fyn kinase may
lead to the common pathological processes that underlie the
development of neurodegenerative disease, including MS,
ALS, AD and PD and will explore the potential of Fyn as a
potentially universal therapeutic target to prevent, reduce or
treat disease progression in these degenerative conditions.
Structure of Fyn
Fyn is 59 kDa in size and is encoded by the Fyn gene,
situated on chromosome 6q2 [7, 13]. Fyn is known to exist
in three active isoforms: Fyn-B, Fyn-T and Fyn-D7 [14,
15]. Fyn-B is broad in its expression in the body, but it is
found in particularly high levels in the brain [14]. Mean￾while, Fyn-T and Fyn-D7 are generally found in cells of
haematopoietic origin and peripheral blood mononuclear
cells, respectively [14, 15]. As it is a member of a large
SFK family, Fyn also shares similar structural properties
with the other SFK members (Src, Lyn, Yes and Lck) [16].
Fyn consists of four Src homology (SH) domains
(SH1–SH4), which are well conserved between SFK mem￾bers, in addition to a Fyn-specifc unique domain (Fig. 1).
At the N-terminus end is the very short SH4 domain, capa￾ble of undergoing fat modifcation, which allows Fyn to
anchor itself at the hydrophobic cell membrane [17]. The
Fig. 1 Schematic representation of Fyn. The multidomain Fyn
structure extends from an N-terminus to a carboxyl (C)-terminus,
with multiple domains in between the terminuses, each with its own
specifc functionality. The Src homology (SH) 4 (SH4) domain at the
N-terminus anchors Fyn to the cell membrane [17]. The subsequent
domain, referred to as the unique region, is poorly conserved amongst
SFK members and thus allows for Fyn-specifc functions [21, 22].
Both the SH3 domain and its neighbouring SH2 domain are capable
of binding to signalling molecules within the cell. However, the SH2
domain also serves as the binding site for a phosphorylated Y531
motif when Fyn is in its inactive state. Connecting the SH2 and SH1
domains is the proline-rich linker region that can interact with the
SH3 domain to form an inactive conformation during Fyn’s inactive
state. The linker region is followed by the catalytic SH1 domain that
is well conserved amongst all SFK members. This particular domain
includes the Y420 motif; the phosphorylation of which is essential for
Fyn activation. Equally important for the regulation of Fyn activation
is the Y531 motif, located on the C-terminus [7, 10, 21, 23]. Figure
created in (2021)
SH4 domain is followed by a unique domain, consisting of
the Y28 motif, which is phosphorylated by platelet-derived
growth factor (PDGF) receptor, leading to activation of
Fyn. Interactions within this domain are integral for focal
adhesion targeting and cell migration [18], as well as for
regulating B cell activity in the adaptive immune system
[19, 20].Beyond this lies the catalytic region of Fyn, con￾sisting of the SH1, SH2 and SH3 domains, as well as the
regulatory C-terminus end.
The regulation of Fyn activity is facilitated by the
dynamic phosphorylation status of both the Y531 motif on
the C-terminus and the Y420 motif on the SH1 domain’s
activation loop [24–26]. In Fyn’s basal state, the Y531
residue on the C-terminus is phosphorylated and forms an
intramolecular interaction with the SH2 domain. Similarly,
the SH3 domain interacts with the linker region, located
between the SH1 and SH2 domains. This results in a folded
conformation that restricts both the SH2 and SH3 domains
from binding to their substrates, thus preventing any external
protein interactions [7, 10, 21, 23]. This inactive Fyn con￾formation is also aided by the dephosphorylation of Y420
in the SH1 domain [10, 27].
In contrast, upon dephosphorylation of the Y531 motif,
the Y531-SH2 intramolecular complex is disrupted, gener￾ating an open conformation that allows for Fyn activation
[28]. This is further enhanced by the autophosphorylation
of the Y420 motif in the SH1 domain [10, 21, 27]. The open
conformation makes the SH2 and SH3 domains accessible to
a broad range of substrates for interaction, allowing Fyn to
function as a major upstream signalling mediator in various
intracellular processes [12, 29, 30]. Recent investigations
have allowed for a deeper understanding of Fyn within the
nervous system. As such, it has also unveiled Fyn’s poten￾tial role in neuronal signalling pathways linked to multiple
neurodegenerative conditions.
Multiple Sclerosis
Multiple sclerosis is a chronic demyelinating disease char￾acterised by progressive loss of the myelin sheath surround￾ing neurons of the CNS [31]. Although the specifc cause
remains unclear, studies strongly point to the aberrant activa￾tion of both the innate and adaptive immune system in the
pathophysiology of the disease [32]. This results in upregu￾lation of the infammatory response and subsequent auto￾immune initiated attack of the myelin sheath, specifcally
by targeting myelin-forming oligodendrocytes, inducing
apoptosis and necrosis [33]. Fyn is known to be expressed
by oligodendrocytes [34] and has been implicated in the
diferentiation and maturation of oligodendrocytes and their
subsequent myelinating functions, as well as in modulation
of the immune response, suggesting that dysfunction of Fyn
may play a role in the pathophysiology of MS [35–37]. In
support of this, genome-wide association studies have impli￾cated single-nucleotide polymorphisms of the Fyn gene in
susceptibility factors associated with MS [38]. Here, we out￾line evidence for Fyn kinase modulation as a potential novel
therapeutic target for MS.
During normal development, oligodendrocytes proliferate
from oligodendrocyte precursor cells (OPCs), which then
undergo terminal diferentiation and initiate process forma￾tion in order to become functional myelinating cells [39].
With demyelination a key pathological hallmark of MS,
remyelination is a vital natural repair mechanism to miti￾gate extensive loss [40]. Initial processes require OPCs to
migrate from the subventricular zone (SVZ) to the damaged
area and diferentiate into mature cells, which are disrupted
in MS [41], and we propose that this may be at least partially
driven by alterations in Fyn activity.
Seminal work by Bare and colleagues [42] identifed that
the peak of Fyn activity in the CNS corresponds with the
peak of myelination in the developing brain. Subsequent
work by Umemori and colleagues revealed Fyn-defcient
mice demonstrated reduced myelination, further solidifying
a role of Fyn in myelinating mechanisms [37]. Fyn activa￾tion is one of the earliest diferentiation triggers, with Fyn
activity 10–30 times higher in mature oligodendrocytes [39,
Fyn assists in the migration of OPCs, mediating the
PDGF activation of cyclin-dependent kinase 5 (CDK5)
and generating the rearrangement of the actin cytoskeleton
that facilitates migration [44]. Indeed, OPC diferentia￾tion requires stable axonal contact in order to successfully
achieve maturation, which is also largely coordinated by
cytoskeleton interactions, such as actin flaments and micro￾tubules [45]. During diferentiation, extracellular matrix
(ECM) integrins binding on OPCs interact with the cyto￾plasmic SH2 Fyn domain, leading to Fyn activation (Fig. 2)
[46]. In turn, Fyn activation phosphorylates Rho family
guanosine triphosphatase (GTPase) proteins (p190RhoGAP
and p250RhoGAP) [46]. Rho family GTPases control cel￾lular morphology via ‘molecular switches’, with binding of
GDP representing an ‘of’ state and GTP representing an
‘on’ state. Fyn activation promotes increased expression of
RhoGDP (or the ‘of’ state’), inactivating RhoA, allowing
hyperextension of oligodendroglial processes and thereby
enabling oligodendrocyte diferentiation and subsequent
maturation [47]. Netrin-1 has also been implicated in this
process, with the binding of Netrin-1 to its receptor (deleted
in colorectal cancer (DCC)) resulting in the recruitment
and activation of Fyn and a subsequent decrease in RhoA
activity, further facilitating increased process extension and
elaboration [48].
Interestingly, in addition to promotion of GDP, Fyn acti￾vation also upregulates GTP (or the on state). When an axon
is initially linked to an oligodendrocyte for myelination, the
axonal ECM protein laminin-2 binds to the extracellular
domain of the oligodendroglial integrin. Fyn associates
intracellularly with the integrin, resulting in its phosphoryla￾tion and the subsequent activation of Rho family GTPases.
This cascade facilitates actin dynamics, promoting mem￾brane rufing and the development of lamellipodia, allowing
the oligodendrocytes to make contact with axons [47, 49].
In support of this, inhibition of Fyn activity has been shown
to block morphological diferentiation of OPCs into mature
oligodendrocytes, a process which has been linked to its role
in the integrin-Fyn-GTPase transduction pathway [39, 47].
In addition to actin dynamics, Fyn activity may also pro￾mote oligodendrocyte maturation via its association with
tau at the SH3 domain, helping to regulate the assembly of
microtubules and consequently contributing to the formation
of the cytoskeleton of oligodendrocytes [45, 50, 51]. During
development, the F3 adhesion molecule on oligodendrocytes
forms a complex with Fyn within lipid rafts, inducing the
phosphorylation of Fyn tyrosines (Y531 and Y420) [52].
Fyn tyrosines bind both to tau and another cytoskeleton pro￾tein, α-tubulin, which subsequently recruit microtubulin to
the contact area, facilitating arborisation and stabilisation of
oligodendroglial processes and orchestrating the axon-glial
contact vital for their maturation (Fig. 2) [52–54]. In line
with this, overexpression of tau deletion protein in cultured
oligodendrocytes has been shown to reduce both the length
and number of processes, likely due to disruption of Fyn-tau
binding [53].
Fyn-Tau interactions mediating microtubule assembly
also facilitate movement of cargo, such as myelin, towards
the axon and the production of myelin itself [55, 56]. Spe￾cifcally, Fyn is prominent in the production of myelin basic
protein (MBP), the major protein in the myelin sheath, and
Fig. 2 Overview of the role of Fyn in physiological processes asso￾ciated with myelination and T cell-mediated infammation. Actin
dynamics—Fyn phosphorylation increases RhoGTPase activity,
downregulating RhoA and altering actin dynamics to allow hyper￾extension of oligodendroglial processes, enabling diferentiation,
maturation, and axonal contact. Microtubule assembly—Fyn tyros￾ines bind to tau and α-tubulin, stabilising oligodendroglial processes,
orchestrating axon-glial contact, and facilitating transport of myelin
towards the axon. Myelin basic protein—contactin/integrin complex
activates Fyn in lipid rafts, phosphorylating the MBP mRNA QK1
protein, leading to granular dissociation and subsequent synthesis
of MBP. Growth factors—BDNF phosphorylates Fyn, activating the
MAPK signalling pathway and promoting myelin growth. Within T
cells—Fyn is required for T cell development and subsequent difer￾entiation of CD4+T cells, which infltrate the CNS and diferentiate
depending on APC to produce infammatory cytokines. Figure cre￾ated in (2021)
is critical for its formation and maintenance [37]. Previ￾ous work has demonstrated a ~ 50% reduction of MBP in
Fyn−/− mice compared to wild-type mice [37]. Mechanisti￾cally, production of MBP is controlled by a contactin/inte￾grin complex within oligodendrocytes, which facilitates
the activation of Fyn in lipid rafts [55]. Activated Fyn then
phosphorylates the MBP mRNA binding quaking (QKI) pro￾tein, leading to granular dissociation and subsequent syn￾thesis of MBP (Fig. 1) [57]. In support of this, suppression
of Fyn activity blocked the translation of MBP that would
normally be induced by neuronal stimulation [58].
Finally, Fyn promotes oligodendrocyte myelination via
interaction with growth factors, including BDNF [59]. Peck￾ham and colleagues recently demonstrated in vitro that, in
oligodendrocytes, BDNF stimulates the autophosphoryla￾tion/activation of Fyn during myelination, consequently
activating extracellular signal-regulated kinases (Erk) 1/2,
part of the mitogen-activated protein kinase (MAPK) signal￾ling pathway [59]. Erk 1/2 activation promotes rapid myelin
growth to increase myelin thickness (Fig. 2). Whilst the
underlying mechanisms are still unclear, this could also link
back to Fyn’s role in the phosphorylation of the Rho family
GTPase protein p190RhoGAP, which also regulates proteins
known to infuence the Erk1/2 pathway [60]. Evidence sug￾gests BDNF is critical to repair the structural integrity of
damaged myelin observed in MS [61].
Given that failure of remyelination in MS is strongly
linked to failure of OPC diferentiation and subsequent abil￾ity to myelinate axons, modulation of Fyn activity may thus
represent a novel therapeutic target, capable of facilitating
the diferentiation and maturation of OPCs via phosphoryla￾tion of GDP and GTP protein and decreasing RhoA expres￾sion. Indeed, RhoA expression has been spatially associ￾ated with MS lesions, with inhibition posed as a potential
therapeutic target [62]. Fyn may also prevent accumulation
of myelin debris, which is linked to disease severity. This
is driven by protein-misfolding, including via increased
deamination of MBP, where arginine amino acids are con￾verted into citrulline. Increased deimination of MBP is seen
in Fyn-defcient mice [63, 64], and thus may be prevented
with increased Fyn activity.
Role of Fyn in T Cell Regulation in MS
Upregulation of the autoimmune response has been impli￾cated in the attack of the myelin sheath observed in MS [32].
In particular, the adaptive immune response, where T cells
recognise and attack myelin protein, has been strongly impli￾cated [32]. In addition to its role in myelination outlined
above, Fyn is perhaps best known for its role in immune
function, with extensive evidence establishing Fyn kinase
as an upstream regulator of the adaptive immune response
of both T cells and B cells; however, this review will focus
on T cells specifcally, given their pivotal role in MS patho￾genesis [32].
T cells diferentiate from thymocytes, with Fyn and its
interactions with another SFK, Lck, involved in nearly all
stages of this development [36]. In particular, Fyn and Lck
are critical in pre-T cell receptor signalling, allowing the
progression of naïve thymocytes through the developmental
stages of T cells [36]. This includes progression through the
early thymic diferentiation stages DN1–DN4 and then the
eventual proliferation of CD4+—or CD8+-naïve T cells,
which migrate to scan for foreign peptide ligands, allow￾ing them to become activated during infection (Fig. 2) [36].
Seminal research demonstrated Lck- and Fyn-defcient mice
exhibited an absolute block in transition between the DN3
and DN4 stages of T cell development, preventing prolifera￾tion of T cells [65, 66].
Once matured, CD4+T cells are able to infltrate into the
CNS, where they can diferentiate further, depending on the
cytokines produced by antigen-presenting cells [67]. In nor￾mal regulatory processes, CD4+T cells are associated with
the production of anti-infammatory cytokines, which help
to maintain homeostasis. However, in MS, it is postulated
that MBP, as well as other myelin proteins, act as antigens,
leading to the priming and activation of autoreactive myelin￾specifc CD4+T cells and the release of pro-infammatory
cytokines, such as IL-23 and IL-17 [68]. These promote a
shift to the T-Helper 17 (Th17) phenotype and an associated
upregulation of the infammatory response exacerbating tis￾sue damage [69]. Fyn has been implicated in the promotion
and regulation of Th17 cells, with Fyn−/− mice exhibiting
decreased levels of IL-17 [70]. This alone would suggest
inhibition of Fyn may assist in downregulation of the infam￾matory response in MS and benefcial efects for the disease;
however, as discussed, Fyn is crucial for CD4+diferen￾tiation to produce benefcial anti-infammatory cytokines
and complete inhibition may therefore negatively afect
this response, suggesting that a more nuanced approach is
Decades of studies have provided evidence of the rela￾tionship between Fyn and healthy neuronal/oligodendro￾glial connections. At present, the specifc role of Fyn in MS
has not been thoroughly characterised; however, parallels
may be drawn based on current understanding of its role
in myelination and T cell regulation more broadly. In MS,
the best approach to targeting Fyn activity is likely to be
highly dependent on the mechanism you aim to modify. For
example, attempts to remyelinate via increased OPC migra￾tion, maturation and myelination, or to reduce the inhibitory
efects of pathological MBP aggregation, suggest upregula￾tion of Fyn may be benefcial. In contrast, to mitigate the
infammatory-induced neurodegeneration observed in MS,
Fyn inhibition may be required. Thus, it is necessary to
role Fyn plays in the time course of the disease, in order to
develop an optimal therapeutic approach.
Alzheimer’s Disease
Pathologically, AD is characterised by the abnormal mis￾folding and aggregation of two key proteins, amyloid beta
(Aβ) and hyper-phosphorylated tau [71]. Pathological accu￾mulation of these proteins promotes excitotoxicity in AD,
leading to the subsequent neurodegeneration observed in
the disease [72, 73]. Shirazi and colleagues frst evaluated
the role of Fyn in the context of human AD and demon￾strated elevated levels of Fyn kinase in the hippocampus of
AD patients [74]. More recently, increased levels of FynT
have been observed in the neocortex of AD patients, a fnd￾ing which was associated with neurodegenerative pathol￾ogy and cognitive impairment [75, 76]. Since, subsequent
studies have demonstrated a key role of Fyn kinase in the
regulation of Aβ, tau and NMDA signalling, leading to the
identifcation of Fyn as a potential novel therapeutic target
for the disease (Fig. 3) [26].
Role of Fyn in Regulating Amyloid‑Beta
and Hyperphosphorylated Tau Production in AD
In AD, cleavage of the APP via the amyloidogenic path￾way through the sequential actions of β- and γ-secretase
leads to the formation of Aβ [77]. Aggregation of these Aβ
monomers into toxic oligomers in AD results in a series
of neurodegenerative alterations throughout the brain that
culminate in impaired long-term potentiation (LTP; a per￾sistent strengthening of synapses) and subsequent neuronal
cell death [78]. Fyn is thought to promote amyloidogenic
processing of APP, via increasing phosphorylation of APP
at Y682 [79]. The Y682 residue in APP is crucial for APP
Fig. 3 Overview of the role of Fyn in physiological and pathologi￾cal processes in Alzheimer’s disease. Fyn phosphorylates the Y682
subunit of APP, promoting amyloidogenic signalling and the aggrega￾tion of Aβ. Aβ aggregates in turn phosphorylate Fyn, where, in the
AD brain, Fyn phosphorylation promotes hyperphosphorylation of
Tau and the formation of neurofbrillary tangles (NFTs). This process
can result in further upregulation of Fyn. Aβ aggregates also bind to
cellular prion receptor protein (PrPc), which phosphorylate Fyn. Col￾lectively, in AD, increased Fyn activity results in hyperphosphoryla￾tion of the NMDAR2B subunit, leading to increased calcium infux
and subsequent excitotoxity. Figure created in (2021)
trafcking in neurons, controlling APP endocytosis and dis￾tribution [80]. Increased phosphorylation at Y682, such as
that induced by Fyn, impairs APP endocytosis, forcing the
accumulation of APP into acidic neuronal compartments,
like the late endosome and lysosomes, where the β-secretase,
BACE-1 is optimally active, promoting the generation of Aβ
peptides. Indeed, overexpression of Fyn promotes amyloi￾dogenic processing of APP [80] and, recently, an increase
in tyrosine phosphorylation of APP was found to be corre￾lated with increased Fyn activity in AD patients [79]. Impor￾tantly, Fyn inhibition was able to prevent increased tyrosine
phosphorylation of APP, with a concomitant decrease in Aβ
secretion in vitro [80].
The amyloid cascade hypothesis suggests excessive extra￾cellular Aβ leads to hyperphosphorylation of the tau protein
[81]. As mentioned earlier, tau is involved in the stabilisa￾tion of cytoskeletal microtubules in the healthy brain [82].
In AD, tau hyperphosphorylation and aggregation leads to
the formation of neurotoxic intraneuronal inclusions called
neurofbrillary tangles (NFTs) in the somatodendritic com￾partment, which destabilise neurons and impair axonal trans￾port [83]. Evidence posits that Aβ-induced tau phosphoryla￾tion may be mediated through Fyn kinase interactions [84,
85]. Mechanistically, the SH3 domain of Fyn binds to tau,
which contains a Fyn specifc phosphorylation site at Y18
[86, 87]. The presence of Aβ dimers sharply increases Fyn
phosphorylation and the subsequent Y18 phosphorylation
of tau, which abnormally accumulates in dendritic spines,
causing NFT formation and eventually leading to neuronal
dysfunction and death [86, 88]. This may occur, at least in
part through the activation of the ERK/S6 signalling path￾way by Fyn. In support of this, co-transfection of tau/Fyn in
HEK293T cells led to activation of the ERK/S6 signalling
pathway and a subsequent, increase in tau levels [85]. Simi￾larly, Aβ oligomers induced somatodendritic accumulation
of tau via activation of the Fyn/ERK/S6 pathway in primary
neurons, in both the APP23 transgenic mouse model of AD
and following stereotaxic injection of Aβ oligomers into the
hippocampus of wild-type mice, an efect that was blocked
following either activity inhibition or genetic deletion of Fyn
Recently, LM11A-31, a small molecule modulator of the
p75 neurotrophin receptor, was found to inhibit tau hyper￾phosphorylation by reducing excess activation of Fyn kinase
both in vitro in neurons exposed to oligomeric Aβ, as well
as in vivo in the APP mouse model of AD [89]. Similarly,
the Src-family kinase inhibitor saracatinib (AZD0530) has
been shown to inhibit okadaic acid-induced tau hyperphos￾phorylation in both mouse neuroblastoma and diferenti￾ated rat primary cortical neuron cultures [90], as well as to
prevent defcits in spatial memory and passive avoidance
learning, with concomitant decreases in hippocampal level
of hyperphosphorylated tau, in transgenic P301S tau mice
[91]. These efects may be due, at least in part, to the inter￾action between the SH3 domain of Fyn and PxxP motifs in
the proline-rich domain of tau. In support of this, a peptide
inhibitor of Tau-SH3 interactions was able to ameliorate
Aβ oligomer-induced toxicity in rat primary hippocampal
neurons [92].
Role of Fyn Kinase in NMDA Receptor Dysfunction
and PrPc Interactions in AD
Accumulation of abnormal aggregates of tau and Aβ is
thought to drive synaptic dysfunction via alterations in LTP
and long-term depression (LTD; a long-lasting decrease
in the strength of synaptic transmission), leading to the
cognitive dysfunction observed in AD [93]. LTP/LTD is
largely mediated by NMDA receptors (NMDAR), which
are tightly regulated by Fyn [94] At rest, the calcium chan￾nel of NMDAR is blocked by Mg2+. In LTP, the strong and
prolonged release of glutamate activates AMPA receptors,
and the subsequent depolarisation removes the magnesium
blockage, allowing infux of calcium and activation of calm￾odulin-dependent protein kinase II-mediated signalling cas￾cade that enhances synaptic strength. Conversely, a modest
activation of NMDARs allows less calcium to enter, trigger￾ing long-term depression and weakening synapses [93]. Fyn
kinase phosphorylates both the NR1A and NR2B subunits
of the NMDA receptor [29, 95]. There are 7 tyrosine resi￾dues on the NR2B C-terminus, with Y1472 the major Fyn
kinase site. Phosphorylation at Y1472 stabilises the synap￾tic localisation of the NMDAR, preventing the interaction
with clathrin adaptor protein and consequent internalisation
[94]. Increased membrane localisation of NMDAR increases
calcium infux and initiates LTP. However, in pathological
conditions, such as AD, this can also mediate excitotoxicity,
promoting excessive calcium infux in response to unregu￾lated glutamate release [96]. Aβ oligomers have been shown
to induce increased phosphorylation of NMDAR via Fyn,
which is believed to contribute to cell death via excitotoxity
[97]. Similarly, tau is also capable of inducing NMDA recep￾tor-dependent calcium infux and subsequent excitotoxicity,
a process which is dependent on Y18 phosphorylation of Tau
by Fyn [98]. Evidence suggests that these processes may be
mediated via cellular prion protein (PrPc) interactions [99].
Whilst the role of PrPc under normal physiological
conditions is not well characterised, it is suggested to be a
response mediator in neurite outgrowth and cell adhesion
[100]. Like Fyn, PrPc is localised to lipid rafts and clustering
of PrPc has been shown to activate Fyn kinase [100, 101].
PrPc signalling is dependent on this Fyn activation, leading
to phosphorylation of signalling cascades which activate
Erks, as well as focal adhesion kinases, such as caveolin-1,
ultimately promoting neurite outgrowth and cell survival
In AD, PrPc has been linked to the binding of Aβ oligom￾ers to neurons [80, 102]. Aβ oligomers can bind with high
afnity to PrPc at the dendritic spines of neurons, leading
to Fyn recruitment and subsequent activation via as-yet￾unidentifed mechanisms [86, 97, 103]. This, in turn, leads
to an increase in the Fyn-specifc phosphorylation of the
glutamatergic NMDA NR2B subunit [104]. As such, over￾expression of PrPc and/or Aβ results in excessive stimula￾tion of glutamate and subsequent increased calcium infux
via Fyn-dependent mechanisms, promoting excitotoxic￾ity and eventually leading to apoptosis [97]. In support of
this, Lacor and colleagues identifed that Fyn activation by
Aβ-PrPc induces excitotoxicity and destabilises dendritic
spines [105]. Whilst Fyn has been demonstrated to be over￾expressed in AD [74], lending merit to this theory, it is not
currently clear if overexpression of Fyn is driving increased
PrPc-Aβ oligomer binding, or if it is rather a consequence
of the abnormal clustering of PrPc observed in AD. This
represents an area for future investigations; however, given
the role of Fyn in the initial cleavage of Aβ peptides, which
predate Aβ oligomer formation, it may be the former.
Much like amyloid, tau is also known to interact with
PrPc in AD [106]. In support of this, a recent 2020 study
established direct binding of tau to PrPc in a range of in vivo
experiments [106]. Further to this, tau-PrPc binding was also
required for disruption of LTP and neurotoxicity. This is
in line with previous evidence from a tau defcient mouse
model, where the detrimental efects of Aβ toxicity could
be blocked by uncoupling Fyn from NMDA receptors and
reducing subsequent neurotoxicity [107]. This may poten￾tially occur by disrupting its co-localisation with tau-PrPc,
although this has not yet been investigated.
Given the fndings discussed above, it is possible that
overactivity of Fyn kinase may play a key role in the patho￾physiology of AD via several diferent mechanisms. Indeed,
the literature suggests Fyn gain of function enhances Alz￾heimer’s disease–related phenotypes, whereas Fyn loss of
function ameliorates Alzheimer’s disease–related pheno￾types [97, 108]. In line with this, Pena and colleagues [109]
found a complete protection of hippocampal neurons from
Aβ-induced toxicity was observed in Fyn−/− mice. Similarly,
overexpression of Fyn has been found to accelerate synapse
loss and induce the onset of cognitive impairment in a trans￾genic murine AD model [108, 110]. Consequently, targeting
Fyn overexpression may represent a therapeutic window for
intervention, with inhibition of Fyn potentially altering early
pathological amyloid signalling in AD.
There are currently several studies which have investi￾gated the efcacy of Fyn inhibition in AD. Animal stud￾ies have identifed that the non-selective inhibition of Fyn
kinase via imatinib derivates increases Aβ clearance, attenu￾ating spatial learning and memory defcits [111]. Similarly,
the Src-family kinase inhibitor saracatinib (AZD0530),
which acts as a reversible ATP inhibitor, has also been
trialled for its potential benefts. Saracatinib inhibits both
isoforms of Fyn with an IC50 value of 8–10 nM, although,
due to homology in the kinase domain, it also inhibits sev￾eral other Src family kinases, including Src (IC50=2.7 nM),
Yes (IC50=4 nM) and Lyn (IC50=5 nM), as well as c-Abl
(IC50=30 nM), a kinase related to the Src family kinases [8,
112]. Saracatinib has demonstrated success in a transgenic
mouse model of AD, where it was able to restore spatial
memory defcits and synaptic depletion [113]. Excitingly,
these benefcial efects were found to persist even after drug
washout [114]. More recently, similarly benefcial efects of
saracatinib for cognitive function were reported in transgenic
P301S tau mice [91]. Saracatinib progressed to a phase 1b
trial in AD, which found the drug was safe and well tolerated
across doses [115]. Disappointingly, however, a subsequent
phase 2a clinical trial revealed no improvements in cerebral
metabolic decline, cognitive impairments or other biomark￾ers in patients with mild Alzheimer dementia, although a
potential trend for a slowing of hippocampal volume and
entorhinal thickness atrophy was observed [116].
Currently, mastinib, a less selective tyrosine kinase
inhibitor that acts on Fyn (IC50 = 240  nM), as well
as CSF-1R (IC50 = 90  nM), c-Kit (IC50 = 200  nM),
PDGF (IC50 = 540  nM), Lyn (IC50 = 500  nM) and Src
(IC50=1.87 μm) [112, 117, 118], is undergoing clinical
trials in AD. In a small placebo-controlled phase II trial,
twice daily administration of mastinib for 24 weeks as an
adjunct to cholinesterase and/or memantine in individuals
with mild-moderate AD led to a slower rate of decline on
the Alzheimer’s Disease Assessment Scale (ADAS-Cog), as
well as improvements on an inventory of activities of daily
living [119]. Despite this, key questions still remain about
the ability of mastinib to inhibit Fyn or cross the blood–brain
barrier and results from the phase III trial (Clinical Trial
Identifer: NCT01872598), originally expected in 2016, have
not yet been released (see [112] for review).
Several other candidates to inhibit Fyn remain to be inves￾tigated for their potential benefts in AD, including dasatinib
(Fyn: IC50=0.2 nM; Lck and Src: IC50=0.4–0.5 nM), a drug
approved for the treatment of chronic myeloid leukaemia
that acts as a selective and potent inhibitor of Src family
kinases [120]. Dasatinib administration reduced microglial
activation in the hippocampus and temporal cortex and
improved performance on the T-maze in the APP/PS1 mouse
model of AD, although Fyn levels were not assessed in this
study [121]. To date, the potential benefts of dasatinib in
individuals with AD remain to be investigated. Nevertheless,
preliminary results indicate a promising potential for the
utility of targeting Fyn kinase to reduce several pathologi￾cal pathways observed in AD, proactively improving cogni￾tive dysfunction by potentially stopping or slowing disease
Parkinson’s Disease
PD is a neurodegenerative disease characterised by a loss
of dopaminergic (DA) neurons in the substantia nigra (SN)
[122]. This is associated with the presentation of motor
impairments, such as resting tremor and akinesia, and a
range of non-motor impairments, such as executive dysfunc￾tion and depression [123]. Fyn kinase may play a direct role
in the activation of the pathways that lead to the degenera￾tion of DA neurons. In support of this, in the MPTP model of
PD, administration of the neurotoxin resulted in Fyn kinase
activation, which subsequently led to phosphorylation and
proteolytic activation of PKCδ-Y311 and initiation of the
apoptotic caspase-signalling cascade that drives the death
of DA neurons [124]. Importantly, inhibition of Fyn using
the p60Src tyrosine-specifc kinase inhibitor (TSKI) peptide
reduced PKCδ-Y311 phosphorylation and protected against
MPP+-induced degeneration in primary DA neurons. Fur￾thermore, MPTP-treated Fyn knockout mice displayed fewer
locomotor defcits, as well as preservation of striatal dopa￾mine levels, reduced degeneration of nigral dopaminergic
neurons and lower levels of PKCδ-Y311 phosphorylation,
compared to MPTP-treated wild-type mice. Similar efects
have also been noted in the DA neuronal N27 cell model
following exposure to the neurotoxic pesticide dieldrin, with
the ability of dieldrin to induce Fyn kinase activation and
subsequent phosphorylation and proteolytic activation of
PKCδ-Y311 almost completely blocked by both pre-treat￾ment with TSKI and selective siRNA-mediated knockdown
of Fyn kinase [125].
Fyn may also play an important role in the interaction
of dopamine with other neurotransmitter systems. Seminal
work by Dunah and colleagues [126] demonstrated that Fyn
is critical for the phosphorylation and subcellular redistri￾bution of striatal NMDA receptors following dopamine D1
receptor activation, with the phosphorylation and trafck￾ing of these receptors tightly regulated by Fyn (for review,
see [94]). Recently, it has been proposed that this may have
implications for the emergence of dyskinesia following treat￾ment of PD with levodopa. Compared to wild-type mice,
Fyn knockout mice displayed reduced levodopa-induced
dyskinesia and lower levels of NMDA NR2B phosphoryla￾tion [127]. Similar results have been observed following
either pre-treatment with saracatinib [127] or, most recently,
intrastriatal administration of a microRNA designed to
silence Fyn [128]. This suggests that, beyond its potential
benefts for treating PD itself, Fyn kinase inhibition may also
represent an exciting new treatment strategy for the treat￾ment of the levodopa-induced dyskinesia frequently associ￾ated with the disease.
Role of Fyn Kinase in Inducing Neuroinfammation
in PD
Whilst the aetiology of PD is unknown, mounting evidence
has identified long-term chronic neuroinflammation as
detrimental long term, contributing to the neurodegenera￾tion observed in PD [129]. Recently, Fyn dysfunction has
been associated with this process [12, 130]. Primarily, the
neuroinfammatory response in the CNS is mediated by
resident immune cells microglia and astrocytes, and, to a
lesser extent, T cells, with Fyn activity established in each
of these cellular processes [12, 131, 132]. Most infuential,
the frst line of immune defence in the CNS is mediated by
microglia [133]. In a healthy brain, the microglial response
is protective and may be downregulated once damage has
been attended to; however, under pathological conditions,
microglia become activated, releasing reactive oxygen
species (ROS), nitric oxide (NO) and pro-infammatory
cytokines, such as tumour necrosis factor-α (TNF-α), inter￾leukin (IL)-1β (IL-1β) and interferon gamma (IFN-γ) [134].
These products further accelerate microglial activation by
binding to their microglial cell surface receptors, sustaining
chronic infammation [135].
The presence of activated microglia in the brains of
post-mortem PD patients has been well established [136,
137] and DA neurons have been identifed as particularly
susceptible to neurodegeneration via protein kinase C delta
(PKCδ) upregulation by microglia [138]. In support of the
role of Fyn in this pathological process in PD, Panicker
and colleagues were frst to link the two, fnding a greater
attenuation of the neuroinfammatory response in Fyn and
PKCδ−/− mice, indicating a crucial role of Fyn kinase as a
major upstream regulator of the infammatory response in
PD and highlighting the potential of Fyn kinase as a target
to mediate this response.
Fyn kinase has been demonstrated to be involved in this
process through its role in microglial activation via the
Fyn-PKCδ signalling axis and NOD-like receptor protein 3
(NLRP3) infammasome (Fig. 4).
Seminal work by Panicker and colleagues [12] charac￾terised the preferential expression of Fyn kinase by micro￾glia. When activated, Fyn is localised from the cytoplasm
to the microglial plasma membrane [12]. Here, an initiating
event, such as a pathogen or pro-infammatory cytokine,
binds to a membrane receptor, such as Toll-like receptor-4
(TLR4), leading to the activation of Fyn. Fyn associates
with PKCδ, upregulating kinase activity and ultimately
enhancing NF-κB activation. When NF-κB is phosphoryl￾ated, components, such as p65, translocate into the nucleus.
p65 translocation and subsequent binding of its subunits
to the promoter of genes initiates the transcription of pro￾infammatory cytokines, such as IL-6 and IL-12, and induc￾ible nitric oxide synthase (iNOS) [138]. Under pathological
conditions, such as those seen in neurodegenerative diseases,
these pro-infammatory cytokines bind to their receptors on
the microglial cell surface, leading to further propagation of
aberrant microglial activation [133]. Studies in cell culture
and transgenic Fyn−/− mice have consistently demonstrated
Fyn is required for cytokine release and activation of iNOS
[12, 132, 139]. More recently, Fyn was also shown to be
critical for upregulation and post-translational modifcation
of Kv1.3, a voltage-gated calcium channel, in microglia
[140]. Kv1.3 may play a key role in sustaining the chronic
neuroinfammatory response seen in PD.
In addition to microglia, Fyn is also expressed to a lesser
extent in astrocytes, with a key role in astrocytic migration
in response to neuronal signals [12, 141]. Astrocytes are
neuroglia also involved in the regulation of the CNS immune
response and, similar to microglia, play both benefcial and
detrimental roles in the brain’s response to insult or injury
[142]. Reactive astrocytes have been linked to patholo￾gies in in the striatum of animal PD models (6-OHDA and
MPTP) and the human PD brain [143]; however, the role of
Fyn in the upregulation of this response in PD has not been
directly investigated. This is likely due to the privileged role
of microglia in this process where, in addition to increased
expression, activated microglia also appear to be required for
the initiation of pro-infammatory astrocyte activity [144].
Fyn kinase, particularly the isoform FynT, plays a role
in the astrocytic-mediated production of pro-infammatory
cytokines (IL-1β and IL-6) via the PKCδ signalling axis,
with Fyn kinase inhibition attenuating the response [145].
This is associated specifcally with chronic exposure to
infammogens, suggesting involvement of astrocytes in a
more chronic insult. Fyn also appears to play a regulatory
role in astrocytic expression of iNOS following infamma￾tory stimulation, with increased iNOS expression in Fyn￾defcient astrocytes [132]. Interestingly, this seems to be in
contrast to Fyn-defcient microglia, where iNOS expression
is decreased [12]. These results suggest Fyn kinase is not
only involved in the upregulation of microglial-mediated
Fig. 4 Overview of the role of Fyn in microglia under infamma￾tory conditions. Initiating event (e.g. α-syn presence/pathogen) binds
to a membrane receptor, leading to activation of Fyn. Fyn upregu￾lates PKCδ activity, leading to the activation of NF-κB and causing
the translocation of the p65 component into the nucleus, leading to
the transcription of pro-infammatory cytokine genes such as IL-1β
(left). Simultaneously, Fyn activation also leads to the internalisation
of α-syn aggregates, priming the NLRP3 infammasome directly and
indirectly (via mitochondrial and lysosomal dysfunction), leading to
the activation and conversion of pro-IL-1β to IL-1β (Figure adapted
from Panicker 2019). Figure created in (2021)
release of iNOS, but may be involved in downregulating
the response in astrocytes. Although yet unclear, this dis￾crepancy between the role of Fyn in iNOS production in
microglia and astrocytes may be due to their diferential
expression of Fyn and PKCδ, with microglia expressing
signifcantly more than astrocytes [12]. Alternatively, this
may be exposure dependent, conditional on the timing of
the infammatory response, or possibly related to diferences
in Fyn isoform splicing [145]; however, this remains to be
As of yet, a clear pathogenesis of PD has not been elu￾cidated and therefore the initiation of the initial infamma￾tory response is not clear; however, current evidence posits
a potential relationship between decreased clearance and
increased spread of ɑ-syn throughout the brain and micro￾glial activation [146, 147]. In PD, microglia have been
recognised as efcient scavengers of misfolded α-syn and
recent evidence suggests the uptake of pathological pro￾teins may be facilitated by Fyn via priming and activation
of the NLRP3 infammasome (Fig. 4). As recently investi￾gated in an elegant series of in vitro and in vivo experiments
by Panicker and colleagues [130], the NLRP3 acts as an
intracellular sensor, detecting danger associated molecular
patterns (DAMPs), such as aggregated α-syn, which bind
to microglia, leading to Fyn activation, transcription of
pro-IL-1β and subsequent microglial activation [130]. This
facilitates the initial uptake of aggregated α-syn by microglia
for phagocytic removal, resulting in the release of mitochon￾drial reactive oxygen species (ROS), lysosomal dysfunction
and priming of the NLRP3 infammasome. Concurrently,
the infammasome is activated, leading to the activation
and conversion of pro-IL-1β to IL-1β [130]. Although this
process is intended to assist in the uptake and degradation
of aggregated α-syn, ultimately, microglial activation has
been shown to hasten α-synuclein dopaminergic neurotoxic￾ity, contributing to disease progression [148]. Furthermore,
evidence in a-syn cultures suggests the ability of activated
microglia to degrade proteins is decreased under infamma￾tory conditions, resulting in the accumulation of internal￾ised aggregates and perpetuating the response [146]. As evi￾dence of this, Fyn−/− microglia display signifcantly reduced
uptake of human α-syn compared to WT microglia [130].
Accordingly, under normal physiological conditions, Fyn
appears to facilitate microglial clearance of aggregated pro￾teins and, as such, Fyn dysfunction may be implicated in the
compromised microglial uptake and degradation observed
under pathological conditions, contributing to PD disease
Taken together with the Fyn/PKCδ pathway of micro￾glial activation, evidence frmly indicates a key role of Fyn
in microglial-mediated neurotoxicity. Thus, Fyn inhibition
may represent a potential therapeutic strategy to reduce
microglial activation via a reduction of pro-infammatory
cytokine genes and maintain efciency of microglial-medi￾ated clearance of α-syn. This may also work in tandem to
reduce astrocyte-mediated neurotoxicity, cumulatively
reducing chronic neuroinfammation and resultant neurode￾generation. To this efect, a crossover study of the phase 2a
clinical trial of Fyn inhibition via saracatinib is currently
underway in a PD population [116]. To date, to the best of
our knowledge, no other study has investigated Fyn kinase
inhibition as a therapeutic strategy for PD.
Fyn: a Common Therapeutic Target Across
Multiple Neurodegenerative Disorders
The literature highlights a specifc role of Fyn in pathologi￾cal processes associated with MS, AD and PD, respectively;
however, it is important to note that there are several com￾monalities between these pathophysiological mechanisms
across diferent neurodegenerative disease (Fig. 5). For
example, although the T cell immune response is prominent
in MS pathology, T cell activity is altered in both AD in PD.
Specifcally, increased CD4+T cells have been observed
in AD [149], and α-syn pathology in PD has been linked to
CD4+T cell infltration into the brain parenchyma [150].
The role of Fyn in T cell dysfunction in AD and PD is yet
to be investigated; however, it is possible that Fyn kinase
inhibition may also serve to restore the T cell response in
these diseases.
Similarly, much like AD, PD is also associated with path￾ological protein aggregation [122]. In PD, ɑ-synuclein mon￾omers misfold, aggregate and form oligomers and fbrils,
accumulating intracellularly to form inclusions called Lewy
bodies (LB) which cause progressive dysfunction and neu￾ronal death [122, 151, 152]. Interestingly, ɑ-syn is structur￾ally and functionally similar to Aβ [153]. Consequently, in
addition to Aβ, ɑ-syn oligomers have also been shown to
interact with PrPc at the post-synaptic density, forming a
complex which phosphorylates Fyn, leading to the activation
of the NR2B subunit in the hippocampus and subsequent
excitotoxicity [152, 154]. Importantly, inactivation of PrPc
prevented the toxic efects of α-syn on synaptic function, a
response authors attributed to the prevention of Fyn/NR2B
signalling and the reestablishment of Ca2+ homeostasis
[152]. This suggests that cell autonomous Fyn kinase inhi￾bition in PD, in addition to reducing neuroinfammation,
could also play a key role in preventing pathological PrPc
Chronic neuroinfammation has also been implicated in
pathology across neurodegenerative diseases, including AD
and MS [155]. Although the role of Fyn has not been specif￾cally investigated in neuroinfammatory processes in these
diseases, it is likely that, similar to what is observed in PD,
the Fyn- PKCδ signalling pathways are also implicated. For
example, fbrillar Aβ has been implicated in the activation of
Fyn and the subsequent promotion of microglial activation
and macrophage migration, with disruption of this pathway
shown to inhibit the macrophage infammatory response to
Aβ and reduce recruitment of microglia to sites of Aβ depo￾sition [156, 157]. Furthermore, the NLRP3 infammasome
has also been linked to pathology in MS [158] and AD [159].
Thus, Fyn inhibition may also serve to reduce abnormal neu￾roinfammation observed in these diseases. Excitingly, Fyn
inhibition using saracatinib has also recently been shown
to reduce neuroinfammation and decrease spontaneously
recurring seizures and epileptiform spikes in a rat kainate
model of temporal lobe epilepsy, suggesting that targeting
Fyn may have utility as a therapeutic strategy beyond neu￾rodegenerative disease alone [160].
Finally, another emerging area of research linking mecha￾nisms common across neurological processes is the role of
Fyn downstream of striatal-enriched tyrosine phosphatase
(STEP), an enzyme believed to oppose SP by providing a
tonic break for synaptic transmission [161]. STEP is highly
expressed in the striatum, cortex, hippocampus and amyg￾dala and regulates LTP and LTD through the internalisa￾tion of NMDARs and AMPARs [162]. STEP counteracts
Fyn activation, with increased STEP activity leading to the
inactivation of Fyn and internalisation of the NR2B subu￾nit, impairing memory consolidation [27, 163]. With regard
to AD, increased STEP activity in the dentate gyrus of the
hippocampus was associated with reduced levels of active
Fyn in an animal model of AD [108]. This is potentially
linked to Aβ, where soluble Aβ signalling has been shown
to dephosphorylate STEP, upregulating its activity [164].
Recent studies have linked increased STEP activity to cog￾nitive decline in AD [108], with cognitive function in AD
Fig. 5 Overview of Fyn dysfunction in neurodegenerative diseases
and potential commonalities.  Multiple sclerosis—increased Fyn
is implicated in the production of pro-infammatory cytokines via T
cell-mediated infammation. Its role in the promotion of myelination
is well established; however, alterations to Fyn activity in MS are
currently unknown.  Alzheimer’s disease—increased Fyn phospho￾rylation is associated with pathological Aß cleavage which hyper￾phosphorylate tau, leading to the formations of NFTs. Aß aggregates
binds to PrPc, phosphorylating Fyn. Collectively, increased Fyn
phosphorylation drives NMDA dysfunction and excitotoxicity.  Par￾kinson’s disease—increased Fyn phosphorylation is required for the
infammatory response in PD mediated by glial cells (astrocytes and
microglia). “+” indicates potential common pathological processes
observed across diseases in which Fyn may play a role in mediating.
Figure created in (2021)
mice signifcantly improved with a decrease in STEP activity
[165]. Similarly, upregulated STEP activity and subsequent
Fyn dysfunction has also been linked to the overexpression
of risk genes of PD such as PARK2, with STEP upregulated
in the striatum of the human PD brain [166]. Given the simi￾larities in pathological protein accumulation in AD and PD,
α-syn may interact in a similar fashion to Aβ, upregulating
STEP, decreasing Fyn kinase activity and increasing NR2B
endocytosis. In support of this, overexpression of α-syn in
transgenic mice has recently been shown to promote cal￾cineurin activity, one of the proposed mechanisms in AD
for Aβ-induced STEP activation [167]. Despite these initial
fndings, however, it is still difcult to understand the exact
role that STEP-Fyn interactions may play in the pathophysi￾ology of these neurodegenerative disorders. Furthermore,
it is difcult to reconcile the cognitive defcits seen due to
downregulation of Fyn in response to increased STEP activ￾ity with the results of studies suggesting benefcial efects of
Fyn inhibition in these diseases. In light of this, signifcant
research remains to be done to answer these key questions.
Conclusions and Future Investigations
Converging lines of evidence suggest Fyn dysfunction may
be involved in neurodegenerative disease pathology and, as
such, targeting Fyn activity may be a promising strategy for
intervention (Fig. 5)
With regard to MS, pharmacological interventions aimed
at remyelination appear to take on two approaches, the neu￾tralisation of diferentiation inhibitors and strategies to pro￾mote the stimulation of oligodendrogenesis [40, 41]. For the
former, pharmaceutical upregulation of Fyn activity may
neutralise the inhibitory efects of myelin debris on remy￾elinating processes. Furthermore, with the latter, upregu￾lation may also be benefcial in several crucial aspects of
oligodendrogenesis promotion, with increased Fyn activity
required for the migration of OPCs to damaged sites [46,
48], the facilitation of actin dynamics permitting oligoden￾drocyte maturation and contact with axons [47, 52, 53], and
the subsequent production of myelin proteins [37, 57, 59].
Furthermore, Fyn in also involved in T cell diferentiation,
specifcally pro-infammatory cytokine release via Th17
[70]. Taken together, logical therapeutic intervention would
aim to increase Fyn activity to promote remyelination in
early disease processes to improve functional recovery, par￾ticularly in relapsing/remitting MS where it may prevent or
shorten the periods of relapse. This needs to be approached
with caution, however, given the purported role of Fyn in
neuroinfammation, where increased Fyn levels have been
associated with increased microglial activation in the PD
brain [130]. Accordingly, with neuroinfammation prevalent
in MS, it is important to characterise the role of Fyn in the
time course of MS pathologies specifcally, or risk potential
exacerbation of disease pathology.
Conversely, in both AD and PD, the current body of evi￾dence promotes the inhibition of Fyn as a therapeutic target
for pathological protein-induced toxicity and neuroinfam￾mation. Namely, inhibition of Fyn may interrupt Fyn-PrPc-
ɑ-syn/Aβ signalling, perturbing protein aggregation and oli￾gomeric binding, which would otherwise result in impaired
neuronal communication and cell death. Current studies
using Fyn kinase inhibitors discussed above have followed
this approach, and whilst efcacy has been established in
animal models of AD, merits of this approach have not yet
been investigated in PD. Furthermore, given the key role that
Fyn may play in the upregulation of the microglial and astro￾cytic activation, Fyn kinase may represent a universal target,
not just in AD and PD, but also across multiple conditions
known to be associated with a chronic neuroinfammatory
response, including ALS [168], stroke [169], traumatic brain
injury [170] and status epilepticus [160].
Given the entirety of the literature in the current space,
when discussing Fyn as a potential target, it is important to
consider and refne dosage due to potential adverse events
stemming from its diverse role in normal neurological func￾tions. For example, whilst Fyn inhibition may be an ideal
route to target disease progression driven by pathological
protein internalisation/aggregation and neuroinflamma￾tion, it may not be ideal for other crucial processes, such as
CNS myelination or SP. Furthermore, Fyn’s role in SP may
mean cognitive function in Fyn inhibition studies needs to
be monitored closely, due to the unique balance of NMDA
activity required for LTP and LTD and the potential of
glutamate-driven excitotoxicity. Fortunately, studies utilis￾ing Fyn kinase inhibitors, such as mastinib and saracatinib,
have demonstrated a much lower level of kinase inhibition
is required to modify the infammatory pathway [6, 115].
In summary, there are currently no disease-modifying
treatments for neurodegenerative diseases and symptomatic
relief for impairments across the diseases is limited. Given
the signifcant and increasing burden to both the afected
individuals and the wider community, it is vital that potential
targets are identifed for intervention. Evidence highlights
Fyn kinase as performing critical roles in the CNS and sug￾gests Fyn dysfunction is involved in pathological signalling
cascades underlying several neurodegenerative diseases,
including MS, AD and PD. Here, we have highlighted the
potential utility of Fyn as a treatment for neurodegenerative
diseases by outlining its involvement in pathways associ￾ated with pathological disease progression in MS, AD and
PD. Subsequently, targeting Fyn kinase activity may repre￾sent a promising target for therapeutic intervention. Whilst
Fyn’s involvement in many neurological signalling cascades
has been well defned, future work is needed to character￾ise Fyn expression and alterations across diferent stages o
pathological progression in neurodegenerative diseases, in
order to better understand the ideal therapeutic window and
Author Contribution BG performed the literature search and drafted
the manuscript. SS contributed to the writing of the manuscript. SM
and FC supervised the project and edited the manuscript. LECP con￾ceptualised the research question independently confrmed the results
of the literature search, supervised the project, and substantially edited
the manuscript.
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