REVIEW Open Access
Biological unc ion o Lemu y osine
kinase 2 (LMTK2): implica ions in
neu odegene a ion
János Bencze
1†
, Gábo Miklós Mó o z
2†
, Woosung Seo
1
, Vik o Bencs
1
, János Kálmán
3
,
Ch is ophe Cha les John Mille
2
and Tibo Ho obágyi
1,4,5,6*
Abs ac
Neu odegene a i e diso de s a e equen , incu able diseases cha ac e ised by abno mal p o ein accumula ion
and p og essi e neu onal loss. Despi e hei g owing p e alence, he unde lying pa homechanism emains
unclea . Lemu y osine kinase 2 (LMTK2) is a membe o a ansmemb ane se ine/ h eonine-p o ein kinase amily.
Al hough i was desc ibed mo e han a decade ago, ou knowledge on LMTK2’s biological unc ions is s ill insu icien .
Recen e idence has sugges ed ha LMTK2 is implica ed in neu odegene a ion. A e e iewing he li e a u e, we
iden i ied h ee LMTK2-media ed mechanisms which may con ibu e o neu odegene a i e p ocesses: dis up ed axonal
anspo , au hype phospho yla ion and enhanced apop osis. Mo eo e , LMTK2 gene exp ession is dec eased in an
Alzheime ’s disease mouse model. Acco ding o hese ea u es, LMTK2 migh be a p omising he apeu ic a ge in nea
u u e. Howe e , u he in es iga ions a e equi ed o cla i y he exac biological unc ions o his unique p o ein.
Keywo ds: Alzheime ’s disease, Axonal anspo , LMTK2, Neu odegene a ion, Tau
In oduc ion
Neu odegene a ion is cha ac e ised by i e e sible s uc-
u al and unc ional damage o neu ons leading o ex ensi e
cell dea h in nume ous cen al ne ous sys em diso de s.
Acco ding o he a ec ed cen al ne ous sys em egions, a
wide ange o clinical symp oms (e.g. demen ia, mo emen
diso de , e c.) can be obse ed. In de ini ion, demen ia is an
acqui ed, p og essi e cogni i e decline se e e enough o
make di icul ies in daily-li e [1]. Alzheime ’sdiseaseis he
mos equen neu odegene a i e demen ia wi h a p e a-
lence o 26.6 million [2]. The e a e se e al and ela i ely
common neu odegene a i e diso de s (e. g. amyo ophic
la e al scle osis) whe e he neu onal damage a ec s o he
egion o he cen al ne ous sys em (i.e. mo o neu ons)
al hough some o ms o mo o neu on diseases a e also ac-
companied by cogni i e impai men s and demen ia [3,4].
Conside ing he ac ha clinical symp oms usually appea
in elde ly, excep in uncommon amilial o ms, p e alence
will undoub edly inc ease in he nex ew decades. P ince
e al. ha e p edic ed ha he numbe o pa ien s wi h de-
men ia will double e e y 20 yea s eaching 115.4 million
globally by 2050 [5]. This endency in ou aging socie y
may aise demen ia o he mos challenging public heal h
issue o he medical and social ca e sys em in he u u e.
Despi e hei signi icance, neu odegene a i e diseases a e
s ill incu able. The a ailable he apies a e limi ed o mi i-
ga ion and me e delay o clinical symp oms. The e o e, in-
ensi e s udy o he ield is essen ial o e eal he
unde lying pa homechanism and o iden i y new he a-
peu ic a ge s o d ug de elopmen . The e is eme ging
e idence ha al e a ions in he le el o synap ic p o eins
and in hei egula ion a e highly in ol ed in he molecu-
la pa hogenesis [6–9], and clinical symp oms [10–12]o
neu odegene a i e diso de s.
LMTK2, a b ain en iched neu onal kinase has ecen ly
become o in e es in neu odegene a i e disease esea ch
since i egula es a numbe o undamen al cellula pa h-
ways linked o neu odegene a ion. These include links
o cyclin-dependen kinase 5 (CDK5)/p35, glycogen syn-
hase kinase-3β(GSK3β), p o ein phospha ase-1 (PP1)
* Co espondence: [email p o ec ed]
†
Equal con ibu o s
1
Di ision o Neu opa hology, Ins i u e o Pa hology, Facul y o Medicine,
Uni e si y o Deb ecen, Nagye dei k . 98, Deb ecen H-4032, Hunga y
4
MTA-DE Ce eb o ascula and Neu odegene a i e Resea ch G oup,
Deb ecen, Hunga y
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Bencze e al. Molecula B ain _#####################_
h ps://doi.o g/10.1186/s13041-018-0363-x
and also he axonal anspo machine y [13–16]. The e-
o e, changes in LMTK2 exp ession and ac i i y may dis-
up synap ic egula o y p ocesses and axoplasmic low
o synapses leading o synap ic dys unc ion, and neu o-
degene a ion. Al hough ou cu en knowledge on he
biological unc ions o LMTK2 is limi ed compa ed o
many o he kinases, we aimed o p o ide a b ie e iew
o he li e a u e and o delinea e LMTK2’s po en ial ole
in neu odegene a i e pa hology.
Cha ac e is ics o LMTK2
LMTK2 was o iginally desc ibed by h ee g oups inde-
penden ly using yeas wo-hyb id sc eens and da abase
sea ch [14,16,17]. The gene o LMTK2 has been
mapped on human ch omosome 7q21.3 and encodes a
p o ein wi h molecula weigh o 250 kDa. Due o pa al-
lel disco e ies, LMTK2 is also known as kinase/phos-
pha ase/inhibi o -2, CDK5/p35- egula ed kinase, b ain-
en iched kinase, apop osis-associa ed y osine kinase-2
and KIAA1079 [14,16–19]. LMTK2 is a membe o he
s uc u ally unique memb ane ancho ed lemu kinase
p o ein amily along wi h LMTK1A, LMTK1B and
LMTK3 [18,19]. A i s sigh , LMTK2 appea s o be a
dual speci ic y osine-se ine/ h eonine kinase based on
he simila i y o i s kinase domain sequence o o he
y osine kinases. Howe e , i has been demons a ed by
independen s udies ha LMTK2 is a se ine/ h eo-
nine-speci ic kinase and do no a ge y osine esi-
dues [14,17,20]. The e o e, he name ‘lemu y osine
kinase’does no accu a ely e lec he kinase p ope y
o his p o ein. We sugges ‘lemu ail kinase’as new
name ins ead o he misleading and con using ‘lemu
y osine kinase’. In his way, he ac onym LMTK can
be kep ensu ing ha he gene/p o ein naming emains
consis en in he li e a u e.
LMTK2 kinase ac i i y was in es iga ed by in i o
kinase assays and pep ide mic oa ay. In hese expe i-
men s, ecombinan and highly pu i ied LMTK2 p o ein
was used (i.e. no o he kinase was p esen in he eac-
ion) which exhibi ed au ophospho yla ion and also
phospho yla ed a ge p o eins sugges ing ha LMTK2
is a cons i u i ely ac i e kinase [14,20] LMTK2 is
ancho ed in o memb anes by i s andem amino- e minal
ansmemb ane domains in a way ha bo h i s amino-
and ca boxyl- e mini ace owa ds he cy oplasm [21].
The ansmemb ane domains a e ollowed by an amino-
e minal kinase domain and a long ca boxyl- e minal
‘ ail’. This long ‘ ail’inspi ed he ecen ly used name
a e he long- ailed Madagascan lemu s. LMTK2 is p e-
dominan ly bu no exclusi ely exp essed in he b ain
and highly en iched in he hippocampus and ce eb al
co ex [16–19]. In neu onal cells, i is loca ed in he cell
body, along neu i es and in g ow h cones [16–18]. In a-
cellula ly, a p opo ion o LMTK2 is p esen in he Golgi
appa a us and ea ly endosomes [16,22,23]. LMTK2
s a s o be highly exp essed in he i s wo- h ee pos -
na al weeks [16–18] sugges ing i s ole in pos na al
neu onal de elopmen . In suppo o his no ion,
LMTK2 is epo ed o unde go apid, p o ein kinase C
(PKC)-dependen phospho yla ion in PC12 cells ollow-
ing neu onal g ow h ac o (NGF) s imula ion howe e ,
i PKC di ec ly phospho yla es LMTK2 is no known
[17,20]. NGF signalling educes LMTK2 ac i i y which
in u n enhances neu i e ou g ow h indica ing ha
LMTK2 is a nega i e egula o o neu onal di e en i-
a ion [17,20]. Ano he , egula o o LMTK2 kinase ac-
i i y is CDK5/p35 and he de ails o his egula o y
mechanism a e discussed in he nex sec ion below.
In e es ingly, he ca boxyl- e minal ail o LMTK2 con ains
se en p oline-(any esidue-any esidue)-p oline (PxxP) mo-
i s [17]. P o eins wi h PxxP mo i can di ec ly bind o p o-
eins wi h S c homology 3 (SH3) domain [24,25].
Nume ous kinases con ain SH3 domains o in e ac wi h
a ge p o eins ia SH3 domain con aining sca olding p o-
eins [26,27]. The e o e, LMTK2 migh be egula ed by ki-
nases wi h SH3 domains o al e na i ely, LMTK2 can
phospho yla e downs eam a ge s by ec ui ing hem by
i s PxxP mo i s. Al hough his is an a ac i e heo y no
SH3 domain con aining LMTK2 binding pa ne has been
iden i ied ye .
To da e, one LMTK2 animal model has been pub-
lished. LMTK2 knockou mice ha e been ound o be i-
able bu male mice a e in e ile due o azoospe mia [28].
This al e a ion de i es om he de ec ed ma u a ion o
ge m cells, sugges ing ha LMTK2 is also essen ial o
physiological spe ma ogenesis. Howe e , he e ec s o
LMTK2 loss on he ne ous sys em in hese animals has
no been p ope ly s udied and epo ed. In o de o dis-
sec neu onal unc ion o LMTK2, u he LMTK2 ani-
mal models need o be de eloped and in es iga ed.
LMTK2 in e ac ing pa ne s
Al hough a ully de ailed in e ac ing ne wo k o LMTK2
emains o be elucida ed he e a e se e al known
p o ein-binding pa ne s and signalling pa hways which
sugges essen ial ole o LMTK2 in key cellula p o-
cesses. LMTK2 in e ac ing pa ne s include CDK5/p35,
he ca aly ic subuni o p o ein phospha ase 1 (PP1C)
and myosin VI. De ails o hei in e ac ion and po en ial
cellula unc ions a e discussed below.
CDK5/p35
CDKs a e p oline-di ec ed se ine/ h eonine p o ein-
kinases in ol ed in cell cycle and ansc ip ion egula-
ion, neu onal mo phogenesis, and neu onal di e en i-
a ion [29]. LMTK2 in e ac s wi h CDK5 ia binding o
p35, he ac i a o subuni o CDK5 [15,16]. This in e -
ac ion is media ed by a sequence (amino acid 391–632)
Bencze e al. Molecula B ain _#####################_ Page 2 o 9
closely loca ed o he kinase domain o LMTK2 howe e ,
whe e LMTK2 binds o p35 and how his in e ac ion is
egula ed is no known [16]. CDK5 is a unique membe
o he CDK amily. Unlike o he CDKs, CDK5 does no
equi e ac i a ing phospho yla ion by cyclins ins ead i
needs binding o ac i a o p o eins o hei clea ed
coun e pa s p35/p25, o p39/p29 [30,31]. CDK5 has
i al ole in neu onal ma u a ion, mig a ion, synap ic
plas ici y and memo y o ma ion as well as in synap ic
esicle exocy osis by phospho yla ing se e al down-
s eam a ge s [29,31]. CDK5/p35 no only binds o
LMTK2 bu also phospho yla es i on se ine-1418 [15,16].
This phospho yla ion induces inc eased LMTK2 kinase ac-
i i y and simul aneously s imula es i s abili y o phospho -
yla e downs eam a ge s such as PP1C [15]. Thus, LMTK2
oge he wi h CDK5/p35 can egula e key neu onal p o-
cesses which a e i al o p ope neu onal unc ioning.
CDK5 is unc ionally inac i e in non-neu onal issues be-
cause CDK5 ac i a o p35 exp ession is es ic ed o neu-
ons [15,32–34]. Ne e heless, a small amoun o
phospho-LMTK2 se ine-1418 was s ill de ec able in non-
neu onal cells sugges ing ha o he kinases can also ac i-
a e LMTK2 by phospho yla ing LMTK2 se ine-1418 in
non-neu onal issues [15]. In e es ingly, bo h CDK5 and
mi ogen-ac i a ed p o ein kinase (MAPK) a e p oline-
di ec ed se ine/ h eonine p o ein-kinases wi h a e y simi-
la consensus sequences which a e (any esidue)-se ine/
h eonine-p oline-(any esidue)-lysin/his idine/a ginine o
CDK5, and p oline-(any esidue)-se ine/ h eonine-p oline
o MAPK [35,36]. This simila i y ha bo h CDK5 and
MAPK equi e a p oline immedia ely downs eam o he
a ge ed se ine/ h eonine esidue aises he possibili y ha
MAPK migh also a ge he same esidues in LMTK2 as
CDK5. Thus, LMTK2 kinase ac i i y migh no only been
egula ed by CDK5/p35 bu also by MAPK. Indeed, expe i-
men al da a show ha ea ing PC12 cells wi h NGF o
PKC ac i a o inc eases MAPK/CDK speci ic phospho yl-
a ion o LMTK2 howe e , i his inc eased phospho yla ion
was induced di ec ly by MAPK o CDK5 is no known
[17]. To sum up, LMTK2 can phospho yla e and egula e
downs eam a ge s, and play impo an ole in bo h neu -
onal and non-neu onal p ocesses.
PP1C
PP1 is a p o ein se ine/ h eonine phospha ase which is
in ol ed in my iad undamen al cellula unc ions. In e -
ac ing wi h dis inc egula o y subuni s, PP1C con ols
cell cycle, apop osis, glycogen homeos asis, RNA splicing,
p o ein syn hesis, muscle ac i i y and neu onal p ocesses
[37,38]. PP1C binds o p o eins wi h an a ginine- aline-
(any esidue)-phenylalanine mo i , also known as RVxF
mo i [39,40]. LMTK2 con ains a aline- h eonine-
phenylalanine (VTF) mo i close o i s ca boxyl- e minus
and binds o PP1C h ough his mo i [13–15]. Upon
binding o PP1C, LMTK2 phospho yla es i on
h eonine-320 which a enua es he phospha ase ac i i y
o PP1C [13–15]. This PP1C inhibi o y ac i i y o
LMTK2 is acili a ed by CDK5/p35-dependen phospho -
yla ion o LTMK2 on se ine-1418, hus CDK5/p35 and
PP1C oge he wi h LMTK2 unc ion in one common
signalling pa hway [13,15]. In e es ingly, LMTK2 also
binds o inhibi o -2, one o he egula o y subuni s o
PP1C which es ic s PP1C ac i i y when hey in e ac
[14,41]. Thus, LMTK2 egula es PP1C ac i i y and in
his way downs eam cellula p ocesses by wo independ-
en mechanisms phospho yla ing i on h eonine-320,
and complex i wi h inhibi o -2.
Myosin VI
Myosin VI is an ac in-based molecula mo o p o ein in-
ol ed in e og ade anspo o endo- and exocy o ic
memb anes. I is known ha some binding pa ne s o my-
osin VI a e in ol ed in in acellula a ge ing and ec ui -
men o myosin VI [42–45]. Two esea ch g oups
simul aneously iden i ied LMTK2 as a myosin VI binding
pa ne . LMTK2 di ec ly binds o a yp ophan- yp ophan-
y osine (WWY) mo i in he ca boxyl- e minal ail o my-
osin VI. [22,46]. The WWY mo i is he same si e whe e
o he endocy ic adap o p o eins bind o myosin VI how-
e e , how ca goes a e selec ed and hei binding o myosin
VI is egula ed is no known [42,46,47]. LMTK2 binds o
heWWYmo i o myosinVI h ougha egionclose oi s
kinase domain (amino acid 567–773) which o e laps wi h
he p35 binding egion (amino acid 391–632) [16,22]. This
o e lap be ween he esidues whe e myosin VI and p35 as-
socia e o LMTK2 aise he possibili y o compe i ion be-
ween myosin VI and p35 o LMTK2 binding al hough, o
da e, he e is no con i ming expe imen al da a. LMTK2
and myosin VI co-localise in endocy ic and ecycling endo-
cy ic esicle compa men s. Th ough binding o myosin VI,
LMTK2 is essen ial o he endocy ic anspo o ans e -
in ecep o , a ca go o myosin VI [22,23]. In e es ingly,
cys ic ib osis ansmemb ane conduc ance egula o
(CFTR), a chlo ide ion selec i e ion channel which mu a-
ion causes cys ic ib osis, binds no only o myosin VI bu
also di ec ly in e ac s wi h LMTK2 [20,48–50]. In addi ion,
CFTR is also a subs a e o LMTK2. Phospho yla ion o
CFTR on se ine-737 by LMTK2 enhances CFTR endocy o-
sis and hus LMTK2 egula es CFTR a ailabili y on he cell
su ace [20,48]. These indings indica e ha LMTK2 has
signi ican ole in he o ches a ion o endocy ic/ ecycling
machine y oge he wi h myosin VI. Ye , he exac egula-
ion o his mechanism emains o be elucida ed.
Implica ions in neu odegene a ion
LMTK2 is in ol ed in neu onal ou g ow h and de elop-
men , axonal anspo , in acellula esicle a icking,
and apop osis [13,22,23,48,51]. Ye , he p ecise way
Bencze e al. Molecula B ain _#####################_ Page 3 o 9
how LMTK2 o ches a es hese p ocesses emains
undisco e ed. The de e minan al e a ions in neu ode-
gene a ion a e dis up ed axonal anspo , pa hological
accumula ion/agg ega ion o disease-speci ic p o eins
and dys egula ed apop osis which oge he lead o neu -
onal loss [52,53]. Taking in o accoun o biological unc-
ions o LMTK2, he e is a plausible link be ween
LMTK2 and neu odegene a i e p ocesses (Fig. 1.).
LMTK2 is en iched in he b ain sugges ing i s c ucial
ole in he cen al ne ous sys em [16–19]. A ecen
genome-wide gene-exp ession s udy compa ed i e
amyloid and au ansgenic mice lines, and c ea ed a
da abase [54]. P og essi ely dec easing LMTK2 exp es-
sion was ound in he co ex and hippocampus p edom-
inan ly in he au mouse model (Tau P301L) du ing he
disease de elopmen , and his educ ion co ela es wi h
pa hological changes. In con as , in he ce ebellum, in-
c eased LMTK2 exp ession was de ec ed and he ani-
mals did no show any ce ebella Alzheime ’s disease
pa hology [54]. As i is de ailed abo e, CDK5/p35 phos-
pho yla es LMTK2 o ac i a e i [15]. In neu odegene a-
ion linked cellula s ess condi ions, such as β-amyloid
o e p oduc ion o oxida i e s ess, calcium-dependen
cys eine p o ease calpain is ac i a ed, and p o eoly ically
clea es p35 in o p25 and p10 [55–58]. Owing o i s lon-
ge hal -li e, p25 p olongs he ac i e s a e o CDK5
esul ing in inc eased phospho yla ion o downs eam
a ge s [56,59,60]. Howe e , i CDK5/p25 can phos-
pho yla e LMTK2 in he same way as CDK5/p35 is no
known. Al hough he numbe o expe imen al s udies is
Fig. 1 Po en ial LMTK2- ela ed neu odegene a i e mechanisms in Alzheime ’sdisease.Inheal hy cells, CDK5/p35 phospho yla es and ac i a es LMTK2.
Ac i a ed LMTK2 inac i a es PP1C by phospho yla ing i which leads o inc eased inhibi o y phospho yla ion o GSK3β. In physiological condi ions, (A)
CDK5/p35 and GSK3βphospho yla es au. (B)GSK3βalso phospho yla es KLC2 o egula e kinesin-1 based anspo while (C) PP1C inhibi s p o-apop o ic
ac o Bim. Alzheime ’sdisease ela ed neu onal s ess (e.g. β-amyloid, ROS e c.) induces calpain media ed clea age o he CDK5 ac i a o subuni p35 in o
p25andp10.p25p olongsCDK5ac i i y.Whe he CDK5/p25canac i a eLMTK2 in he same way as CDK5/p35 is no known. This and neu onal s ess
ela ed educed LMTK2 exp ession leads o blocked LMTK2 phospho yla ion pa hway. Dis up ed LMTK2 phospho yla ion pa hway causes PP1C
dephospho yla ion and ac i a ion which in u n ac i a es GSK3βby emo ing i s inhibi o y se ine-9 phospho yla ion. (A’) O e ac i a ed GSK3βand
CDK5/p25 abno mally hype phospho yla e au. Abno mal au hype phospho yla ion dis up s au unc ion and mic o ubule ne wo k, a ec s axonal
anspo , and o ms neu o ib illa y angles. (B′)O e ac i a edGSK3βphospho yla es KLC2 esul ing in ca go elease and dis up ed Smad2 anspo and
signalling. (C′) O e ac i a ed GSK3βsup esses an i-apop o ic Bcl-2 and inc eases he p o-apop o ic Bim le els, and signalling. Ac i a ed PP1 inhibi s Bim
howe e , i canno coun e balance GSK3βmedia ed Bim ac i a ion and apop osis. [Colou codes: G een symbols a e unc ionally ac i e, ed symbols a e
inac i e enzymes. No e ha hickness o a ows and colou shades e lec ac i i y le els whe e hin a ows/ligh colou s ep esen low ac i i y, and hick
a ows/da k colou s high ac i i y. Abb e ia ions: Bcl-2 = B-cell lymphoma-2; Bim = Bcl-2-in e ac ing media o o cell dea h; CDK5 = cyclin-dependen
kinase-5; GSK3β= glycogen syn hase kinase-3β; KLC2 = kinesin-1 ligh chain 2; LMTK2 = lemu y osine kinase 2; PP1C = ca aly ic subuni o p o ein
phospha ase-1; ROS = eac i e oxygen species]
Bencze e al. Molecula B ain _#####################_ Page 4 o 9
ce ainly limi ed, based on he known biological unc-
ions and in e ac ing pa ne s, we a emp o p o ide a
b ie explana ion how he p e iously epo ed educed
LMTK2 le els in Alzheime ’s disease animal model, and
po en ially dis up ed phospho yla ion cascade can con-
ibu e he disease pa hology.
Dis up ed axonal anspo
Physiological axonal anspo is undamen al o main-
aining he complex neu onal homeos asis. Neu ons a e
pola ised cells wi h majo i y o hei p o eins syn he ized
in he soma and equi e he e o e well-o ganized in a-
cellula anspo o each hei a ge s. The e a e ou
i al ac o s in his play: mic o ubule acks, molecula
mo o p o eins, ca goes and ene gy in he o m o ATP.
Any dis up ion o his p ecise machine y pe u bs
axonal anspo and causes abe an accumula ion o
p o eins, and o ganelles in di e en neu odegene a i e
pa hologies in demen ias, mo emen diso de s and
mo o neu on diseases, o e iew see [52].
Kinesin-1 is a majo molecula mo o p o ein media -
ing axonal anspo o se e al key ca goes such as mi o-
chond ia, amyloid p ecu so p o ein and synap ic esicle
p ecu so s owa ds synapses [61–64]. Mos unc ional
kinesin-1 is a he e o e ame composed o wo kinesin-1
hea y chains and wo kinesin-1 ligh chains (KLCs).
Kinesin-1 hea y chains mo e along mic o ubules while
KLCs a e mainly in ol ed in ca go binding [62]. Phos-
pho yla ion o KLCs is an impo an ca go binding and
eleasing egula o y mechanism [61,65,66]. GSK3βcan
di ec ly phospho yla e KLC2 o induce ca go elease and
sup ess kinesin-1 media ed anspo [13,65]. In ol e-
men o CDK5 in GSK3β-dependen egula ion o axonal
anspo was i s desc ibed by Mo ini e al. [66]. They
ha e epo ed ha CDK5 indi ec ly egula es GSK3βac-
i i y ia PP1C. Howe e , he na u e o in e ac ion (i.e.
di ec o indi ec ) be ween CDK5/p35 and PP1C was
unclea [66]. Manse and co-wo ke s ha e ecen ly e-
ealed ha LMTK2 is he missing link be ween CDK5/
p35, PP1C and GSK3βwhich b ings hese p o eins o-
ge he in one phospho yla ion pa hway o egula e
kinesin-1 based axonal anspo [13,15]. In his no el
signalling pa hway, CDK5/p35 ac i a es LMTK2 by
phospho yla ing i a se ine-1418. Phospho yla ed
LMTK2 in u n educes PP1C ac i i y by phospho yla -
ing i a h eonine-320. Finally, phospho yla ion o PP1C
h eonine-320 leads o inc eased inhibi o y phospho yl-
a ion o GSK3βa se ine-9 [13,15]. Inhibi ed GSK3βis
no able o phospho yla e KLC2 which p omo es KLC2
binding o ca gos, such as mo he s agains decapen aple-
gic homolog 2 (Smad2). Thus, LMTK2 is a nega i e
egula o o KLC2 phospho yla ion and LMTK2 ac i i y
p omo es kinesin-1 based anspo o Smad2 [13,67].
Smad2 is a ansc ip ion ac o which shu les be ween
he cy oplasm and nucleus, and is a c ucial playe in
ans o ming g ow h ac o -β(TGFβ) signalling pa hway
[68]. TGFβinduces Smad2 ansloca ion in o he nu-
cleus whe e i egula es he exp ession o TGFβ-
esponsi e genes [69]. siRNA knockdown o LMTK2 dis-
up s Smad2 binding o KLC2 and impo an ly, i also
inhibi s TGFβ-induced nuclea signalling o Smad2
p obably due o a ec ed Smad2 anspo [13]. Reduced
LTMK2 gene-exp ession has been de ec ed in an Alzhei-
me ’s disease au mouse model [54]. Addi ionally, al e ed
TGFβ/Smad2 signalling has been obse ed in common
neu odegene a i e diseases, including Alzheime ’s dis-
ease [70,71] sugges ing ha LMTK2 is no only in-
ol ed in he egula ion o kinesin-1 based anspo bu
also can con ibu e he pa homechanism o neu odegen-
e a i e diseases by a ec ing axonal anspo .
Tau hype phospho yla ion
Neu o ib illa y angles a e hallma k in aneu onal
pa hological ea u es o Alzheime ’sdisease.Neu o-
ib illa y angles consis o mis olded and abno mally
hype phospho yla ed au, a mic o ubule-associa ed
p o ein [72,73]. CDK5 and GSK3βa e majo au ki-
nases which a e in ol ed in au hype phospho yla-
ion in i o [74–77]. Al hough bo h CDK5 and
GSK3βa e su icien o hype phospho yla e au,
nega i e co ela ion has been e ealed be ween hei
ac i i ies. I has been shown ha inc eased CDK5 ac-
i i y inhibi s GSK3βby inc easing i s inhibi o y
phospho yla ion a se ine-9 [13,15,66,78,79].
In e es ingly, CDK5 media ed GSK3βinhibi ion is
age dependen . In young mice, GSK3βac i i y is e-
ducedcompa ed oagedmicewhe eGSK3βac i i y
is inc eased causing au hype phospho yla ion [79,
80]. The exac mechanism o age dependen ly en-
hanced GSK3βac i i y and au hype phospho yla ion
is no known. One possible explana ion is ha he
molecula b eaking mechanism which inhibi s GSK3β
ac i i y is de ec i e. P og essi ely dec easing LMTK2
le els seen in an Alzheime ’s disease mouse model
[54] could po en ially lead o abe an o e ac i a ion
o GSK3βin aged mice. I is impo an o no e ha
dec eased LMTK2 le els and/o kinase ac i i y leads
o inc eased PP1C ac i i y [13,15]. I is also known
ha hype phospho yla ed au ilamen s a e able o
ac i a e PP1 [81–83]. PP1 can dephospho yla e au
on some esidues which a e abno mally hype pho-
spho yla ed in Alzheime ’sdisease[84,85]. In ac ,
despi e inc eased PP1 ac i i y, au emains hype pho-
spho yla ed in Alzheime ’s disease sugges ing ha
ele a ed au phospha ase ac i i y o PP1C canno
coun e balance inc eased GSK3βac i i y. The abo e
hypo hesis explains some aspec s o au hype pho-
spho yla ion howe e , i needs u he in es iga ion.
Bencze e al. Molecula B ain _#####################_ Page 5 o 9

Apop osis
A ecen siRNA-based high- h oughpu sc een has iden i-
ied LMTK2 as a po en ial egula o o apop osis [51].
siRNA media ed LMTK2 knockdown dec eases an i-
apop o ic B-cell lymphoma-2 (Bcl-2) and B-cell
lymphoma-ex a-la ge (Bcl-xL), and inc eases p o-
apop o ic Bcl-2-in e ac ing media o o cell dea h (Bim)
p o ein le els [51]. These LMTK2-associa ed al e a ions
made cells mo e sensi i e o oxic e ec s o apop osis in-
ducing ligands and o he cy o oxic compounds. The e ec
o LMTK2 silencing on Bim le els is media ed by in-
c eased PP1C and GSK3βac i i y [51]. Bim le els a e also
dec eased in he b ain o Alzheime ’s disease pa ien s and
Bcl-2 is p o ec i e agains Alzheime ’s disease- ela ed in-
sul s [86,87]. LMTK2 silencing was also accompanied by
dec eased Ak and ex acellula signal- egula ed kinase-1/
2(ERK1/2)ac i i y[51,88–91]. These changes can also
con ibu e o apop osis bu he exac mechanism how
LMTK2 can modula e Ak and ERK1/2 ac i i y is no
known. In essence, hese esul s sugges ha dec eased
LMTK2 le els can sensi ise cells o cy o oxici y ia a ec -
ing apop o ic and su i al pa hways, and i is consis en
wi h he hypo hesis ha educed LMTK2 le els may con-
ibu e o cell dea h in neu odegene a ion.
Acco ding o ou cu en knowledge, he majo i y o
neu ons a e e minally di e en ia ed cells [92]. Howe e ,
ce ain noxious s imuli (e.g. oxida i e s ess, β-amyloid
pep ide, au hype phospho yla ion) can induce abe an
cell cycle eac i a ion [20,29,93–95]. Since neu ons los
hei p oli e a i e capaci y, he abno mal cell cycle e-
en y is in e up ed by di e en egula o y mechanisms
leading o apop osis, o e iew see [95,96]. The e o e,
noxious s imuli which induce uncon olled cell p oli e a-
ion in o he issues could cause ex ensi e cell dea h in
neu onal issue. In neu ons, abe an cell cycle eac i a-
ion up egula es cyclin D and cyclin E exp ession, and in-
c eases he ac i i y o G
1
and G
2
phase CDKs [97–102].
Inc eased CDK ac i i y esul s in e inoblas oma p o ein
phospho yla ion and concomi an E2F elease in neu ons
[99,102,103]. E2F p omo es he exp ession o p o-
apop o ic genes and ansac i a es downs eam cell cycle
genes igge ing he p og ession o he le hal apop o ic
cycle [104]. Conside ing LMTK2 as umou supp esso /
p o-apop o ic p o ein, i is possible ha E2F educes
LMTK2 le els by ansc ip ional silencing. Suppo ing his
heo y, se e al s udies ha e epo ed dec eased LMTK2
exp ession in bo h neu odegene a ion and cance [54,
105,106]. Ne e heless, he po en ial link be ween E2F
and he LMTK2 gene has ye o be explo ed.
Conclusion and p ospec s
P e alence o neu odegene a i e diseases a e exponen-
ially inc easing in ou aging socie y. Conside ing ha
hese equen pa hologies mos ly a ec he elde ly, i is
c i ical o p o ide an e ec i e solu ion o his u gen
issue. Al hough ou knowledge is s ill insu icien , he
la es s udies poin owa d o he same di ec ion:
LMTK2 is in ol ed in neu odegene a ion (Table 1.)
Despi e he limi ed amoun o s udies in he ield,
LMTK2 seems o be mis- and down egula ed in Alzhei-
me ’s disease. The e o e, manipula ion o he p o ein
le el could be a p omising no el he apeu ic a ge . A
ecen s udy has iden i ied a 2-O-Te adecanoylpho bol-
13-ace a e (TPA) esponsi e elemen in LMTK2 gene
[110]. TPA is a syn he ic PKC ac i a o wi h abili y o
inc ease LMTK2 exp ession. The mechanism equi es
ac i a o p o ein-1 ansc ip ion ac o complex binding
o LMTK2 p omo e egion in which he complex is
ans-ac i a ed by p o ein kinase C [110]. These esul s
a e p obably aluable bu ce ainly no su icien o
d ug de elopmen . Thus, u he comp ehensi e in es i-
ga ions a e essen ial o e eal and o unde s and he
unc ion o LMTK2 in neu odegene a i e p ocesses.
Abb e ia ions
Bcl-2: B-cell lymphoma-2; Bcl-xL: B-cell lymphoma-ex a-la ge; Bim: Bcl-2-
in e ac ing media o o cell dea h; CDK5: Cyclin-dependen kinase 5;
CFTR: Cys ic ib osis ansmemb ane conduc ance egula o ; ERK1/
2: Ex acellula signal- egula ed kinase-1/2; GSK3β: Glycogen syn hase kinase-
3β; KLC: Kinesin-1 ligh chain; LMTK2: Lemu y osine kinase 2;
MAPK: Mi ogen-ac i a ed p o ein kinase; NGF: Neu onal g ow h ac o ;
PKC: P o ein kinase C; PP1: P o ein phospha ase-1; Smad2: Mo he s agains
decapen aplegic homolog 2; TGFβ: T ans o ming g ow h ac o -β; TPA: 2-O-
Te adecanoylpho bol-13-ace a e; VTF: Valine- h eonine-phenylalanine;
WWY: T yp ophan- yp ophan- y osine
Table 1 Gene exp ession s udies o LMTK2 in neu odegene a ion
Disease Resea ch model Disease sample Con ol sample LMTK2 gene
exp ession in disease
sample
S a is ical
signi icance
Re e ence
Alzheime ’s
disease
Mouse issue Tau P301L co ex and
hippocampus
Wild- ype co ex
and hippocampus
Dec eased No known [54]
Pa kinson’s
disease
Human issue Subs an ia nig a Subs an ia nig a
om con ols
Dec eased No known [107]
Amyo ophic
la e al scle osis
Human emb yonic s em
cell-de i ed mo o neu on
Neu ons exposed o mu an SOD1
as ocy e condi ioned medium
Non- ea ed
neu ons
Dec eased No known [108]
Hun ing on’s
disease
Mouse issue DE5 (D9-N171-98Q) s ia um Wild- ype s ia um Dec eased Yes (p=
0,025)
[109]
Bencze e al. Molecula B ain _#####################_ Page 6 o 9
Acknowledgemen s
No applicable.
Funding
Suppo ed by he ÚNKP-17-3 New Na ional Excellence P og am o he
Minis y o Human Capaci ies and EFOP-3.6.3-VEKOP-16-2017-00009 (JB);
GINOP-2.3.2–15–2016-00043 and Hunga ian B ain Resea ch P og am (2017–
1.2.1-NKP-2017-00002) (TH); KTIA_NAP_13–1–2013-0001 (JK); BBSRC (BB/
L019299/1) (CCJM) and ARUK (CCJM and GMM).
A ailabili y o da a and ma e ials
No applicable.
Au ho s’con ibu ions
Concep ion and design o he s udy by JB, TH and GMM. P ima y d a by JB
aided by VB and WS. Re isions by GMM and TH, amended by JK and CCJM.
All au ho s ha e ead and app o ed he inal e sion.
E hics app o al and consen o pa icipa e
No applicable.
Consen o publica ion
No applicable.
Compe ing in e es s
The au ho s decla e ha hey ha e no compe ing in e es s.
Publishe ’sNo e
Sp inge Na u e emains neu al wi h ega d o ju isdic ional claims in
published maps and ins i u ional a ilia ions.
Au ho de ails
1
Di ision o Neu opa hology, Ins i u e o Pa hology, Facul y o Medicine,
Uni e si y o Deb ecen, Nagye dei k . 98, Deb ecen H-4032, Hunga y.
2
Depa men o Basic and Clinical Neu oscience, Ins i u e o Psychia y
Psychology and Neu oscience, King’s College London, London, UK.
3
Depa men o Psychia y, Facul y o Medicine, Uni e si y o Szeged, Szeged,
Hunga y.
4
MTA-DE Ce eb o ascula and Neu odegene a i e Resea ch G oup,
Deb ecen, Hunga y.
5
Depa men o Pa hology, Facul y o Medicine,
Uni e si y o Szeged, Szeged, Hunga y.
6
Depa men o Old Age Psychia y,
Ins i u e o Psychia y Psychology & Neu oscience, King’s College London,
London, UK.
Recei ed: 1 Feb ua y 2018 Accep ed: 26 Ma ch 2018
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