Brainiac Caspases: Beyond the Wall of Apoptosis

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). F on ie s in Cellula Neu oscience | www. on ie sin.o g 1No embe 2019 | Volume 13 | A icle 500 ncel-13-00500 No embe 2, 2019 Time: 13:9 # 2 Espinosa-Oli a e al. Caspases in he CNS 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; F on ie s in Cellula Neu oscience | www. on ie sin.o g 2No embe 2019 | Volume 13 | A icle 500 ncel-13-00500 No embe 2, 2019 Time: 13:9 # 3 Espinosa-Oli a e al. Caspases in he CNS 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). F on ie s in Cellula Neu oscience | www. on ie sin.o g 3No embe 2019 | Volume 13 | A icle 500 ncel-13-00500 No embe 2, 2019 Time: 13:9 # 4 Espinosa-Oli a e al. Caspases in he CNS 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 F on ie s in Cellula Neu oscience | www. on ie sin.o g 4No embe 2019 | Volume 13 | A icle 500 ncel-13-00500 No embe 2, 2019 Time: 13:9 # 5 Espinosa-Oli a e al. Caspases in he CNS 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). F on ie s in Cellula Neu oscience | www. on ie sin.o g 5No embe 2019 | Volume 13 | A icle 500 ncel-13-00500 No embe 2, 2019 Time: 13:9 # 6 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). 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No use, dis ibu ion o ep oduc ion is pe mi ed which does no comply wi h hese e ms. F on ie s in Cellula Neu oscience | www. on ie sin.o g 9No embe 2019 | Volume 13 | A icle 500