ncel-13-00500 No embe 2, 2019 Time: 13:9 # 1
MINI REVIEW
published: 05 No embe 2019
doi: 10.3389/ ncel.2019.00500
Edi ed by:
Vic o ia Campos-Peña,
Na ional Ins i u e o Neu ology
and Neu osu ge y (INNN), Mexico
Re iewed by:
Jo ge Ma ias-Guiu,
Complu ense Uni e si y o Mad id,
Spain
Dwayne G. S upack,
Uni e si y o Cali o nia, San Diego,
Uni ed S a es
*Co espondence:
Miguel Angel Bu guillos
[email p o ec ed]
Special y sec ion:
This a icle was submi ed o
Cellula Neu opa hology,
a sec ion o he jou nal
F on ie s in Cellula Neu oscience
Recei ed: 27 June 2019
Accep ed: 22 Oc obe 2019
Published: 05 No embe 2019
Ci a ion:
Espinosa-Oli a AM,
Ga cía-Re illa J, Alonso-Bellido IM
and Bu guillos MA (2019) B ainiac
Caspases: Beyond he Wall
o Apop osis.
F on . Cell. Neu osci. 13:500.
doi: 10.3389/ ncel.2019.00500
B ainiac Caspases: Beyond he Wall
o Apop osis
Ana Ma ía Espinosa-Oli a, Juan Ga cía-Re illa, Isabel Ma ía Alonso-Bellido and
Miguel Angel Bu guillos*
Depa amen o de Bioquímica y Biología Molecula , Facul ad de Fa macia, Uni e sidad de Se illa, and Ins i u o
de Biomedicina de Se illa (IBiS), Hospi al Uni e si a io Vi gen del Rocío/CSIC, Se ille, Spain
Fo he las wo decades, caspases, a amily o cys eine-aspa ic p o eases, ha e
e ol ed om being conside ed solely as egula o s o apop osis o in lamma ion o
ha ing a wide ange o unc ions. In his mini e iew, we ocus on he mos ecen
“non-apop o ic” oles o caspases in he CNS, pa icula ly in neu ons, as ocy es and
oligodend ocy es. Non-apop o ic caspase unc ions in mic oglia ha e al eady been
e iewed ex ensi ely elsewhe e. He e we discuss he in ol emen o caspases in he
ac i a ion o he in lammasome, au ophagy, and non-apop o ic o ms o cell dea h
such as nec op osis and py op osis. Also, we e iew he in ol emen o caspases in
synapses and he p ocessing o agg ega es key o neu odegene a i e diseases such as
Pa kinson’s, Alzheime ’s and Hun ing on’s diseases. Likewise, we men ion he ecen ly
desc ibed in ol emen o caspases in mi ochond ial biogenesis, which is a unc ion
independen o he enzyma ic ac i i y. We conclude discussing he ele ance ha “new”
unc ions o caspases ha e in he CNS and he u u e o his ield o esea ch.
Keywo ds: caspase, neu on, as ocy es, oligodend ocy es, in lammasome, nec op osis, neu odegene a ion,
py op osis
INTRODUCTION
Caspases a e a amily o p o eins belonging o he cys eine aspa a e p o eases classically associa ed
wi h di e en o ms o p og ammed cell dea h (S ennicke and Sal esen, 1999;Hyman and Yuan,
2012;Tumme s and G een, 2017).
Since he disco e y o CED-3 in Caeno habdi is elegans (Ellis and Ho i z, 1986) and he caspase-
1/In e leukin-1 con e ing enzyme (ICE) (Tho nbe y e al., 1992;Yuan e al., 1993), caspases
we e g ouped based on hei unc ion as “apop o ic” o “in lamma o y.” This classi ica ion has
emained use ul o some ex en un il ecen ly, since new non-apop o ic o non-in lamma o y oles
ha e su aced o caspases (Shalini e al., 2015;Baena-Lopez e al., 2018;Holl ille and Deshmukh,
2018). Besides, o e he las decade, e idence has been ga he ed de ailing non-apop o ic oles o
caspases in as ocy es, neu ons, oligodend ocy es (ODCs) and mic oglia (Aca in e al., 2007;Li
e al., 2010;Bu guillos e al., 2011;Wagne e al., 2011).
The aim o his mini- e iew is o p o ide an upda e on he a ious unc ions o caspases ( om
hose desc ibed o e wo decades ago, o ecen unc ions desc ibed wi hin he las 5 yea s) in he
CNS, ocusing mainly on neu ons, as ocy es and ODCs (see Table 1). We will only b ie ly discuss
mic oglia cells as we ecen ly published an in-dep h e iew on his opic (Shen e al., 2018).
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TABLE 1 | Non-apop o ic unc ions o caspases in di e en cell ypes.
Cell ype Model and caspase in ol ed Re e ences
In lammasome As ocy es P ima y co ical as ocy es om mice wi h Aβ1−42 (caspase-1)Eb ahimi e al., 2018
P ima y glial cul u es om WT, Nl c4−/−, Nl p3−/−and Asc−/−mice wi h
LPC(caspase-1)
F eeman e al., 2017;
Human p ima y as ocy es wi h ATP (caspase-1)Minkiewicz e al., 2013
SOD1 mouse model/ALS pa ien s (caspase-1)Johann e al., 2015
In ace eb al hemo hage mouse model (caspase-1)Wang e al., 2017
Mouse p ima y as ocy es wi h me hamphe amine (caspase-11)Du e al., 2017
Mic oglia EAE mouse model (caspase-8)Zhang e al., 2018
Neu ons P ima y cul u es o human neu ons unde se um-dep i ed condi ions (caspase-1)Kaushal e al., 2015
APPSwe/PS1dE9 ansgenic mice (caspase-1)Tan e al., 2014
Dopamine gic neu ons om PD pa ien s (caspase-1) on He mann e al., 2018
ODCs Adminis a ion p ena al o dexame hasone o mice (caspase-1)Ma u ana e al., 2017
Py op osis As ocy es Ischemia induced by he oxygen-glucose dep i a ion in p ima y cul u ed as ocy es
om a s (caspase-1)
Xia e al., 2018
S oke model in a s (caspase-1)
Cul u ed a co ical as ocy es wi h bili ubin (caspase-1)Feng e al., 2018
Sepsis model in mice and a s induced by LPS (caspase-1)Li e al., 2019;Sun e al., 2019
Neu ons Neu ons P ima y cul u es o human neu ons unde se um-dep i ed condi ions (caspase-1)Kaushal e al., 2015
Cul u ed co ical neu ons om a s wi h Aβ(caspase-1)Tan e al., 2014
SCI model in a s (caspase-1, caspase-11)Lin e al., 2016;de Ri e o
Vacca i e al., 2008
Caspase-1-/- mice subjec ed o con olled co ical impac inju y (caspase-1)Liu e al., 2018
Ischemic s oke model in mice (caspase-1,caspase-11)Fann e al., 2018
Ocula hype ension-inju ed e ina in mice (caspase-1)P onin e al., 2019
ODCs EAE mouse model (caspase-1)McKenzie e al., 2018
MS pa ien s (caspase-1)
Nec op osis ODCs EAE and Cup izone mouse models o MS and in MS pa ien s (caspase-8)O engeim e al., 2015
Osmo ic demyelina ion synd ome model in mice (caspase-8)Boucha e al., 2018
Neona al a s subjec ed o hypoxia-ischemia (caspase-8)Qu e al., 2017
Neu ons Global ce eb al ischemia/ epe usion in CA1 neu ons in a s (caspase-8)Xu e al., 2016
Suba achnoid hemo hage induced b ain inju y model in a s (caspase-8)Chen e al., 2018;
Yuan e al., 2019
Models o e inal degene a ion in a s (caspase-8)Jang e al., 2019
As ocy es Mouse spinal co d as ocy es wi h LPS o TNF-αwi h zVAD (caspase-8)Fan e al., 2016
SCI model in mice (caspase-8)
Mic oglia Mice s e eo axically injec ed wi h LPC (caspase-8)Lloyd e al., 2019
Synapses Neu ons Cul u ed neu ons subjec ed o neu o ophic ac o dep i a ion (caspase-3,
caspase-6,caspase-9)
Simon e al., 2012
Caspase-3 knockou mice (caspase-3)E ü k e al., 2014
J20 APP ansgenic mice (caspase-2)Pozue a e al., 2013
Caspase-9−/−mice (caspase-9)Ohsawa e al., 2010
Caspase-3−/−neona al mice (caspase-3)Gu e al., 2017
Caspase-3 knockou mice and a s (caspase-3)Li e al., 2010
Tg2576-APPSwe mice (caspase-3)D’Amelio e al., 2011
Au ophagy Neu ons P ima y co ical neu ons om w and casp2−/−mice wi h o enone (caspase-2)Tiwa i e al., 2011
PC12 cells and co ical neu ons om a s wi h Aβ1−42 (caspase-3)Wang e al., 2017
APPSwe/PS1dE9 ansgenic mice (caspase-3)
Mi ochond ia
Biogenesis
Neu ons Dopamine gic cell line (p ocaspase-3)Kim e al., 2018
Caspases In lammasome and Py op osis
The in lammasome (Ma inon e al., 2002) is a mul ip o ein
in acellula complex ha senses pa hogenic mic oo ganisms and
s e ile s esso s, which ul ima ely p ocesses and eleases IL-1β
and IL-18. The ac i a ion o he in lammasome consis s o
a wo-s ep pa hway (Fi s s ep: TLR ac i a ion; Second s ep:
e.g., ATP). This leads o caspase-1, caspase-11 (de Ri e o
Vacca i e al., 2014;Walsh e al., 2014;B oz and Dixi , 2016;
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Voe e al., 2019) and caspase-8 (Zhang e al., 2018) ac i a ion.
Also in acellula lipopolysaccha ide (LPS) may bind di ec ly
o caspase-11, p omo ing i s ac i a ion (Shen e al., 2018).
In lammasomes a e ca ego ized as canonical (caspase-1) o non-
canonical (caspase-11) (B oz and Dixi , 2016) ( o he gene al
signaling pa hway, see Figu e 1A). In mic oglia cells, a ecen
s udy desc ibed a non-canonical in lammasome associa ed o
caspase-8 (and independen ly o caspase-1), in which mic oglia
we e able o gene a e IL-1βin an Expe imen al au oimmune
encephalomyeli is (EAE) mouse model (Zhang e al., 2018).
This inding is con adic o y o a p e ious s udy done in
Bone Ma ow De i ed Mac ophages (BMDM), whe e caspase-
1 de iciency is necessa y o caspase-8 p ocessing and elease o
IL-1β(Schneide e al., 2017).
The ac i a ion o he in lammasome can e ol e in o a p ocess
o egula ed cell dea h e med py op osis, which ac s as a
de ense mechanism agains in ec ion by inducing pa hological
in lamma ion (Tai e al., 2014). In py op osis, bo h caspase-1
and caspase-11 (caspase-4 and caspase-5 in humans) ha e been
desc ibed as media o s o his ype o cell dea h ( o he gene al
signaling pa hway, see Figu e 1A;Aglie i e al., 2016;P onin
e al., 2019).
In lammasomes we e o iginally desc ibed in immune cells
(Shen e al., 2018) hough he p esence o he in lammasome
in o he cells han mic oglia in he CNS has been epo ed
oo. In as ocy es, c ucial egula o s o he immune esponses
in he inju ed CNS, he p esence o canonical and non-
canonical in lammasomes occu s upon ea men wi h di e en
s imuli in i o (Minkiewicz e al., 2013;Du e al., 2017;
F eeman e al., 2017;Eb ahimi e al., 2018). In i o, high
exp ession le els o nucleo ide-binding oligome iza ion domain-
like ecep o p o ein (NLRP) 3 ela ed o he neu oin lamma o y
esponse has been ound in as ocy es o SOD1 mice and in
Amyo ophic la e al scle osis (ALS) pa ien s (Johann e al., 2015).
Also, di e en s udies showed as ocy ic py op osis in animal
models o sepsis induced by LPS (Li e al., 2019;Sun e al., 2019).
Besides mic oglia and as ocy es, he p esence o di e en
ypes o in lammasomes ha e been epo ed in non-immune
ela ed cells, such as neu ons (Figu e 1B and Table 1).
O e 10 yea s ago, he exis ence o NACHT leucine- ich-
epea p o ein 1 (NALP1) neu onal in lammasome was epo ed
(Kumme e al., 2007). Since hen, se e al s udies ha e
demons a ed ha ac i a ion o he in lammasome occu s
in neu ons, ollowed no mally by cell dea h induced by
py op osis. In he con ex o Alzheime ’s disease (AD), py op osis
occu s upon amyloid-β(Aβ) ea men in i o, as well
as in i o in he APPSwe/PS1dE9 mice. In bo h cases,
ei he knockdown o NLRP1 (ano he ype o in lammasome)
o caspase-1 con e ed neu op o ec ion (Tan e al., 2014).
In e es ingly, in a ecen s udy, NLRP3 in lammasome was
cha ac e ized in dopamine gic neu ons om Pa kinson’s disease
(PD) pa ien s ( on He mann e al., 2018). In his s udy he
au ho s iden i ied, ia exome sequencing, a single-nucleo ide
polymo phisms (SNPs) o NLRP3 which esul s in a less
soluble o m o NLRP3 p o ein han NLRP3 wild- ype.
This less soluble o m was associa ed wi h a signi ican ly
educed isk o de eloping PD, highligh ing he ele ance
o NLRP3 in lammasome in dopamine gic neu ons in PD
( on He mann e al., 2018).
In a ecen s udy by Tsuchiya e al. (2019), he au ho s
desc ibed how i was possible o al e he ype o neu onal dea h
( om py op osis o apop osis), based on he le els o exp ession
o Gasde min D (GSDMD). GSDMD is a speci ic subs a e o
caspase-1, -4, -5 and -11, whose N- e minal clea age p oduc
has a po e- o ming ac i i y ha causes cell swelling and lysis
ia py op osis. In his sense, co ical neu ons may die h ough
apop osis ins ead o py op osis a e oxygen-glucose dep i a ion
(OGD) and nige icin s imula ion due o low exp ession o
GSDMD (Tsuchiya e al., 2019).
Finally, in ODCs, he ele ance o in lammasome
ac i a ion has no been as well documen ed, wi h only a
ew epo s published. Fo ins ance, p ena al adminis a ion
o dexame hasone o mice, a ea men ha p omo es
demyelina ion, induces NLRP3, caspase-1 and Apop osis-
associa ed speck-like p o ein con aining a CARD (ASC)
exp ession in ODCs, which he au ho s sugges ed could be
con ibu ing o demyelina ion (Ma u ana e al., 2017). Also,
py op osis has been obse ed in myelin- o ming ODCs in
he EAE mice and in pa ien s wi h Mul iple scle osis (MS)
(McKenzie e al., 2018). In his case, inhibi ion o caspase-1,
using he inhibi o VX-756, educed py op osis in ODCs
and mic oglia and p omo ed neu op o ec ion and imp o ed
pe o mance in di e en neu obeha io al es s. In his case is
ha d o dis inguish i VX-756 bene icial e ec o e beha io is
based on inhibi ion o in lammasome and/o py op osis o bo h.
Caspases and Nec op osis
O iginally nec op osis was conside ed a passi e dea h o cells
unde pa hological condi ions, whe e he cellula con en s a e
eleased and cause an immune esponse. Howe e , cu en ly i is
conside ed a cell dea h pa hway egula ed h ough he in e ac ion
o di e en molecules including ecep o -in e ac ing p o ein
kinase (RIPK)-1 and RIPK3, mixed lineage kinase domain-like
p o ein (MLKL), and caspase-8 (whose ac i i y is inhibi ed o
ins ance by caspase-8 o pan-caspase inhibi o s) (Figu e 1A;Tai
e al., 2014;O engeim e al., 2015).
Nec op osis media es ODC degene a ion induced by TNF-
α, whose binding o TNFR1 igge s caspase-8 ac i a ion, and
he inhibi ion o RIPK1 p o ec s agains ODC cell dea h in wo
animal models o s udy MS, and also in cell cul u e (O engeim
e al., 2015). In he same pape , he au ho s ound in co ical
lesions o human MS samples de ec i e caspase-8 ac i a ion and
ac i a ion o RIPK1, RIPK3, and MLKL. Also in a di e en
in i o model o osmo ic demyelina ion synd ome, ODC cell
dea h has been linked o nec op osis based on an inc ease o
phospho-MLKL immuno eac i i y (Boucha e al., 2018), bu
u he expe imen s a e needed o con i m his esul .
In he de eloping b ain, a s udy showed ha neona al a s
subjec ed o hypoxia–ischemia (HI) and ODCs om neona al
a s ea ed wi h OGD oge he wi h he pan-caspase ac i i y
inhibi o zVAD die ia nec op osis (Qu e al., 2017). T ea men s
aimed o block he in e ac ion o RIPK3 wi h MLKL o CaMKIIδ,
a new desc ibed subs a e o RIPK3, managed o dec ease
nec op osis unde hese condi ions (Qu e al., 2017).
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FIGURE 1 | Non-apop o ic oles o caspases in in lammasome, py op osis and nec op osis in he CNS. (A) Le panel ep esen s he gene al mechanisms o igge
bo h canonical and non-canonical in lammasome ac i a ion and subsequen py op osis. Also, i is included he ecen ly desc ibed caspase-8 dependen
non-canonical in lammasome ac i a ion in mic oglia (mglia) and BMDM. Canonical in lammasome commences upon a i s signal (“p iming s age,” 1) induced by
DAMPS o PAMPS ha p omo e he exp ession o he componen s o he in lammasome. Th ee ypes o in lammasome ha e been desc ibed so a (NLRs, AIM2,
and Py in in lammasomes). A second signal (2) is needed o in lammasome assembly ia he p o ein adap o ASC and caspase-1, which becomes ac i e h ough
clea age. Clea ed caspase-1 (Casp-1cl) may ei he clea e p o-IL1βin o IL1β ha will be eleased, o p ocess gasde min D (GSDMD), he known e ec o o
py op osis. In he non-canonical in lammasome, cy osolic LPS, om in acellula G am nega i e bac e ia binds wi h high a ini y o caspase-11, p o oking
sel -assembly and i s ac i a ion. Ac i e caspase-11 indi ec ly p omo es he clea age o he p o-IL1βby ac i a ing he NLRP3 in lammasome and caspase-1.
Mo eo e , caspase-11 is also capable o di ec ly clea e GSDMD o p omo e py op osis. Caspase-8 ge s ac i a ed ia he in lammasome in wo di e en ways
depending on he cell ype. In mic oglia, he in lammasome ge s ac i a ed ia TLR-IRAKM axis, ha p omo es caspase-8 ac i a ion and IL-1β elease. In BMDM, in
he absence o GSDMD o caspase-1 ac i i y, he in lammasome becomes ac i a ed upon Nige icin ea men , also p omo ing caspase-8 ac i a ion and inducing
IL1β elease and delayed cell lysis, ia caspase-3, and independen o GSDMD. Nec op osis ( igh panel) is a p og ammed o m o nec osis commonly igge ed by
umo nec osis ac o ecep o (TNFR) o oll-like ecep o s (TLRs) upon in lamma o y o neu odegene a i e s imuli. Ac i a ion o hese ecep o s leads o
ecep o -in e ac ing se ine/ h eonine-p o ein kinase 1 (RIPK1) disengagemen om he ecep o pla o m and he apid ec ui men o RIPK3 and Casp8 o o m he
ipop osome. A his poin , ac i a ion o caspase-8 will lead o apop osis. Howe e , absence o inhibi ion o caspase-8 will lead o phospho yla ion o bo h RIPK1
and RIPK3 and he ec ui men and phospho yla ion o mixed lineage kinase domain like pseudokinase (MLKL). MLKL phospho yla ion igge s i s oligome iza ion,
gaining po e- o ming ac i i y ha leads o cell lysis. (B) In lammasomes desc ibed in di e en CNS cell ypes desc ibed in his pape .
In e es ingly in neu ons, a new in e ac ion o RIPK3 wi h
he p o ein apop osis-inducing ac o (AIF) has been epo ed.
Thei in e ac ion and ansloca ion in o he nucleus in a model
o 20-min global ce eb al ischemia/ epe usion (I/R) has been
desc ibed in CA1 neu ons, which was c i ical o ischemic DNA
deg ada ion and p og ammed nec osis (Xu e al., 2016). The
ac ha hese CA1 neu ons lack caspase-8 exp ession, acili a es
nec op osis in hese cells.
In as ocy es, a s udy pe o med in mouse spinal co d
as ocy es ea ed wi h LPS o TNF-αwi h zVAD in i o, and
subjec ed o spinal co d inju y (SCI) in i o, showed an inc ease
in he exp ession o RIPK3 and MLKL p o eins (Fan e al., 2016).
T ea men wi h he chemical inhibi o o RIPK1 (Nec os a in-1)
o RIPK3 gene ic abla ion (Fan e al., 2016) escued he cells.
In he case o neu ons, in a model o suba achnoid
hemo hage i has been epo ed ha neu onal dea h occu s
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ia RIPK3 and MKLK (Chen e al., 2018;Yuan e al.,
2019). Mo eo e , inhibi ion o RIPK1 [using RIPK1-inhibi o y
compound (RIC)] in e inal degene a i e diseases induced by
glaucoma ous insul has been p o ed o exe a neu op o ec i e
e ec (Jang e al., 2019).
In iguingly, while nec op osis o neu ons, ODCs and
as ocy es is associa ed no mally wi h demyelina ion and
neu odegene a ion, a new epo in mic oglia cells (Lloyd e al.,
2019) p oposes ha he emyelina ion p ocess in whi e ma e
is d i en by p oin lamma o y mic oglia nec op osis and he
subsequen epopula ion o posi i ely egula ed by ype-1 IFN
signaling mic oglia.
Caspases and Synapses
In he ma u e CNS, caspases a e no only in ol ed in media ing
cell dea h bu also egula o y e en s ha a e impo an
o neu onal unc ions, such as, axon p uning and synapse
elimina ion (D’Amelio e al., 2010;Hyman and Yuan, 2012;
Holl ille and Deshmukh, 2018).
Du ing axonal p uning, he absence o neu o ophic
ac o s p o okes caspase-3/6 ac i a ion ia JNK ha acili a es
mi ochond ial depola iza ion (Holl ille and Deshmukh, 2018).
The ole o caspases in axon p uning has also been s udied
in he con ex o axon degene a ion induced by neu o ophic
ac o dep i a ion in sympa he ic neu ons. Caspase-3, caspase-6
o caspase-9 a e equi ed o he axon selec i e degene a ion
o p uning (Simon e al., 2012) bu no Apa -1 (Cusack e al.,
2013), which is equi ed o igge ing cell dea h upon axonal
Neu onal G ow h Fac o (NGF) dep i a ion. Caspase-3 was
also ound o con ol spine densi y and dend i e mo phology in
speci ic a eas wi hin he cell gene a ing supe nume a y spines
in caspase-3 knockou mice (E ü k e al., 2014). Caspase-
2 pa icipa es in he con ol o dend i e spine densi y ia
ac i a ion o he RhoA/ROCK-II signaling pa hway (Pozue a
e al., 2013). Caspase-2 de iciency in J20 APP ansgenic mice
did no hwa cogni i e unc ion despi e ha ing simila Aβ
load and neu oin lamma o y esponse o wild ype animals
(Pozue a e al., 2013).
Caspases a e also in ol ed in axonal guidance and
synap ogenesis like o ins ance caspase-9-media ed clea age o
Semapho in 7 media es he p ope p ojec ion o axons in senso y
neu ons (Ohsawa e al., 2010). In he spinal co d o neona al
mice, caspase-3 egula es he numbe o axonal b anches ia
Bax/Bak in he axons o co icospinal neu ons. Ea ly pos na al
inac i a ion o Bax/Bak in mo o co ex esul s in inc eased
axonal b anches in he spine o hese animals when hey each
adul hood. As a consequence, connec i i y’s ine- uning is
los and animals ail o acqui e ine olun a y mo emen s
(Gu e al., 2017).
No mal b ain unc ions depend on p ope synap ic ac i i y.
Long- e m po en ia ion (LTP) and long- e m dep ession (LTD)
a e long-las ing modi ica ions o synapses in he hippocampus
egion. Ac i a ion o caspase-3 du ing LTD occu s wi hou
cell dea h (Li e al., 2010;Simon e al., 2012) and acili a es
he in e na ionaliza ion o AMPA ecep o in he pos synap ic
memb ane. Fu he mo e, caspase-3 p omo es modi ica ions in
AMPA- ype ecep o ha lead o al e a ions o glu ama e gic
synap ic ansmission and plas ici y in Tg2576-APPSwe mice.
No ably, pha macological inhibi ion o caspase-3 ac i i y
in hese mice escued he obse ed AD-like pheno ypes
(D’Amelio e al., 2011).
Caspases and Neu o oxic P o ein
Agg ega es
Caspases play a signi ican ole in he pa hogenesis o di e en
neu odegene a i e diseases including AD, PD and Hun ing on’s
disease (HD), since hey a e able o modi y he p ope ies
o di e en neu o oxic p o eins agg ega es (amyloid p ecu so
p o ein (APP), Tau, α-synuclein (α-Syn) and hun ing in (h )
h ough clea age.
Unde apop o ic condi ions, caspases clea e APP, ei he
di ec ly o ollowing γ-sec e ase gene a ion o he AICD
agmen , o gene a e he C31 and Jcasp pep ides [ o mo e
in o ma ion see e iew (Nhan e al., 2015)]. While AICD and C31
a e associa ed wi h cell dea h in i o (Lu e al., 2000;Be and
e al., 2001;Pa k e al., 2009), he impac o his in i o may
be minimal, since mice bea ing mu an caspase- esis an APP
displayed no escue in lea ning o memo y in a mouse model o
AZ (Ha is e al., 2010).
Tau is ano he subs a e p ocessed by caspases ea ly in
he p og ession o AD (Rissman e al., 2004). Clea ed Tau
p omo es nuclea ion-dependen ilamen o ma ion which is
phospho yla ed by glycogen syn hase kinase-3b in a p ocess
media ed by caspase-3 (Chu e al., 2017). Recen ly, i has been
shown ha caspase-2 speci ic clea age in Tau p o okes an
inadequa e so ing o Tau owa d he dend i ic spines, p omo ing
cogni i e impai men and synap ic dys unc ion (Zhao e al.,
2016). In e es ingly, clea age o APP p omo es phospho yla ion
o Tau in di e en esidues, in a p ocess whe e C31 binds o
he aspa agine, p oline, h eonine, y osine (NPTY) mo i o he
ca aly ic subuni o he phospha ase PP2A, ep essing i s ac i i y
(Pa k e al., 2012).
α-Syn is an abundan ly exp essed neu onal p o ein
localized in he p esynap ic e minals o neu ons. α-Syn is
key o unde s anding he e iology o a g oup o o e lapping
neu odegene a i e diso de s called α-synucleinopa hies,
including PD. α-Syn is p ocessed h ough caspase-1 o ming a
unca ed p o ein whose e ec is o accele a e he o ma ion o
agg ega es as compa ed o he ull-leng h o m o α-Syn (Wang
e al., 2016). In e es ingly, unca ed α-Syn i sel s imula es
caspase-1 ac i a ion which p omo es mo e clea age o α-Syn, in
a posi i e eedback loop (Ma e al., 2018).
Finally, caspase clea age o h induces i ’s accumula ion in he
nuclei o neu ons o HD pa ien s (G aham e al., 2010). Caspase-
6 clea es h , and caspase-6 ac i a ion has been obse ed be o e
he onse o mo o abno mali ies bo h in mouse and human
HD b ains (G aham e al., 2010). S ikingly, in i o expe imen s
using YAC mice exp essing caspase-6- esis an clea age o h ,
showed no s ia al neu odegene a ion. Recen ly a new caspase
clea age si e o h has been desc ibed, in his case depending
on caspase-1 ac i i y ha p omo es agg ega ion o mu an h
(Ma in e al., 2019).
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Espinosa-Oli a e al. Caspases in he CNS
While he e idence ga he ed in PD and HD s udies sugges s
ha caspase-dependen p ocessing o α-Syn and h may play a
ole in he pa hogenesis o he diseases, con lic ing esul s o APP
in i o and in i o ha e been obse ed in AD models, equi ing
u he in es iga ion.
Also, he expe imen s o s udy clea age o APP by caspases
ha e been pe o med unde apop o ic condi ions, which makes
di icul o conclude i he caspase clea age o APP plays any
pa hological ole o is jus “colla e al damage” ha occu s du ing
apop osis. Fu he expe imen s unde non-cell dea h condi ions
should be pe o med o esol e his issue.
Caspases and Au ophagy and
Mi ochond ia Biogenesis
Au ophagy is a ca abolic p ocess ha deli e s cy oplasmic
cons i uen s in o lysosome o deg ada ion and e en ual
ecycling. Unde physiological condi ions, au ophagy p omo es
cell su i al by elimina ion o damaged o ganelles and p o eins
agg ega es (Za e-Shahabadi e al., 2015). Howe e , au ophagy
has also been linked o cell dea h, ei he p omo ing i (Das
e al., 2012) o a leas being associa ed wi h i (K oeme
and Le ine, 2008). E idence sugges s ha au ophagy may
be con olled by caspases du ing apop osis (Tsap as and
Nezis, 2017). Howe e , e idence o he in e ac ion be ween
au ophagy- ela ed p o eins and caspases in he CNS a e s ill
sca ce. In p ima y cul u es o co ical neu ons ea ed wi h
o enone, lack o caspase-2 p olonged cell su i al by enhancing
au ophagy. Howe e , he cells die e en ually ia nec osis
(Tiwa i e al., 2011).
A ecen s udy showed ha caspase-3-induced Beclin-1
clea age and subcellula edis ibu ion o he Beclin-1 N- e minal
in o he nucleus has been shown in neu on-glia co-cul u es wi h
Aβ1−42 and APPSwe/PS1dE9 mice. The au ho s hypo hesized
ha clea age o Beclin-1 by caspase-3 could a ec au ophagy
and lead o de ec i e p o ein clea ance and neu onal dea h
(Wang e al., 2017).
Despi e all hese oles ha we ha e discussed in his mini-
e iew, new and exci ing oles a e s ill eme ging o caspases
in he CNS. Fo ins ance, in a ecen s udy pe o med by Kim
e al. (2018) in dopamine gic neu ons, he au ho s desc ibed
how p ocaspase-3 ac s as a egula o o mi ochond ia biogenesis
wi hou a ec ing au ophagy. They showed ha TFAM, N -1, and
PGC-1a ( ansc ip ional ac i a o s o mi ochond ial biogenesis)
a e egula ed by p ocaspase-3. Fu he mo e, in he same s udy,
he au ho s show ha lack o p ocaspase-3 in dopamine gic
neu ons d ama ically educed elec on anspo chain complex
I, II, and IV ac i i y. In e es ingly, ea men wi h caspase-
3 inhibi o ailed o mimic he obse ed e ec s hus aising
he iew ha caspase-3-dependen mi ochond ial biogenesis is
independen o i s ca aly ic ac i i y.
DISCUSSION
Wi hin he las decade, he e has been an exponen ial g ow h in
he numbe o s udies o non-apop o ic unc ions o caspases.
Some o hese non-apop o ic oles ha e been ex ensi ely
s udied in speci ic cell ypes, such as he in lammasome in
immune cells (Ma inon e al., 2002). In he CNS, while
many o hese non-apop o ic unc ions ha e been s udied
in mic oglia cells, ew epo s ha e been published o
neu ons, as ocy es and ODCs in compa ison. He e we
a emp o shed ligh on o some “old and new” non-apop o ic
unc ions o caspases in hese cell ypes, which ha e been
ga he ing momen um in ecen yea s and hei ele ance unde
pa hological condi ions.
Why does he ac i a ion o execu ione caspases no ansla e
always in o an apop o ic p ocess? A possible explana ion
could be seques a ion o e ec o caspases in o di e en
subcellula compa men s (Li e al., 2010;Ka anagh e al., 2014;
Amchesla sky e al., 2018) and/o clea age o non-cell dea h
ela ed subs a es (Aca in e al., 2007).
Di e en manne s in which caspases a ec cellula signaling
con inue o eme ge. Besides he di e se mechanisms employed
o ac i a e di e en caspases al eady commen ed in his
mini- e iew, i has been shown ha he educ ion o he
basal ac i i y o caspase-3 p omo es a change owa d a
umo suppo i e pheno ype in mic oglia cells in con ac
wi h glioma cells (Shen e al., 2016). Also, and in ag eemen
wi h his, in emb yonic s em cells (ESCs), basal caspase-3
ac i i y egula es cell di e en ia ion o hese cells h ough
Nanog p ocessing (Baena-Lopez e al., 2018). We ha e also
discussed p e iously in his mini- e iew how he zymogen
(p ocaspase-3) media es he mi ochond ial biogenesis
independen ly o i s enzyma ic ac i i y (Kim e al., 2018). I
is possible ha hese unc ions o caspase-3 can be ex ended
o o he caspases, opening new possibili ies in he ield
o caspase biology, o new mechanis ic oles o caspases
wi h ele ance no only limi ed o he CNS bu applicable
o all cell ypes.
AUTHOR CONTRIBUTIONS
MB and AE-O concei ed he main ou line. MB w o e he
manusc ip . All au ho s sea ched he e e ences and decided he
con en s o he mini e iew.
FUNDING
JG-R has been unded by a g an om he Spanish
Minis e io de Economia y Compe i i idad SAF2015-64171-
R (MINECO/FEDER, EU). MB has been unded by he Spanish
Minis e io de Economia y Compe i i idad (P og ama Ramón y
Cajal: RYC-2017-21804).
ACKNOWLEDGMENTS
We apologize o colleagues whose wo k we ha e no ci ed he e as
a esul o space limi a ions.
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Espinosa-Oli a e al. Caspases in he CNS
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