PERSPECTIVE
published: 10 Feb ua y 2017
doi: 10.3389/ nins.2017.00039
F on ie s in Neu oscience | www. on ie sin.o g 1Feb ua y 2017 | Volume 11 | A icle 39
Edi ed by:
Cin ia Rood eld ,
Andalusian Molecula Biology and
Regene a i e Medicine Cen e
(CABIMER) - CSIC, Spain
Re iewed by:
Janice E a A lee B aun,
Uni e si y o Calga y, Canada
Kon ad E ns Zinsmaie ,
Uni e si y o A izona, USA
*Co espondence:
Lucia Taba es
[email p o ec ed]
†P esen Add ess:
Elena Lopez-O ega,
Solomon H. Snyde Depa men o
Neu oscience, Johns Hopkins
Uni e si y School o Medicine,
Bal imo e, MD, USA
Special y sec ion:
This a icle was submi ed o
Neu odegene a ion,
a sec ion o he jou nal
F on ie s in Neu oscience
Recei ed: 18 Decembe 2016
Accep ed: 19 Janua y 2017
Published: 10 Feb ua y 2017
Ci a ion:
Lopez-O ega E, Ruiz R and Taba es L
(2017) CSPα, a Molecula
Co-chape one Essen ial o Sho and
Long-Te m Synap ic Main enance.
F on . Neu osci. 11:39.
doi: 10.3389/ nins.2017.00039
CSPα, a Molecula Co-chape one
Essen ial o Sho and Long-Te m
Synap ic Main enance
Elena Lopez-O ega1 †, Rocío Ruiz2and Lucia Taba es1*
1Depa men o Medical Physiology and Biophysics, School o Medicine, Uni e si y o Se ille, Se ille, Spain, 2Depa men o
Biochemis y and Molecula Biology, School o Pha macy, Uni e si y o Se ille, Se ille, Spain
Cys eine s ing p o ein α(CSPα) is a esicle p o ein loca ed in he p esynap ic e minal
o mos synapses. CSPαis an essen ial molecula co-chape one ha acili a es he
co ec olding o p o eins and he assembly o he exocy ic machine y. The absence o
his p o ein leads o al e ed neu o ansmi e elease and neu odegene a ion in mul iple
model sys ems, om lies o mice. In humans, CSPαmu a ions a e associa ed wi h
he de elopmen o neu onal ce oid lipo uscinosis (NCL), a neu odegene a i e disease
cha ac e ized by in acellula accumula ion o lysosomal ma e ial. He e, we e iew he
physiological ole o CSPαand he pa hology esul ing om he homozygous dele ion
o he gene o i s mu a ions. In addi ion, we in es iga e whe he long- e m mode a e
educ ion o he p o ein p oduces mo o dys unc ion. We ound ha 1-yea -old CSPα
he e ozygous mice display a educed abili y o sus ain mo o uni ec ui men du ing
epe i i e s imula ion, which indica es ha physiological le els o CSPαa e equi ed o
no mal neu omuscula esponses in mice and, likely, in humans.
Keywo ds: cys eine s ing p o ein, co-chape one, mo o neu ons, synap ic ansmission, neu omuscula junc ion,
CSPα
PROTEIN DESCRIPTION
Cys eine s ing p o ein α(CSPα) (Dnajc5) is a highly conse ed p o ein (Figu e 1A) ypically
associa ed wi h he memb ane o synap ic esicles and sec e o y g anules (Zinsmaie e al., 1990).
I con ains a DNA-J domain cha ac e is ic o Hsp40 co-chape ones. This domain in e ac s wi h
he 70 kDa hea shock cogna e p o ein (Hsc70) (B aun e al., 1996) and egula es he e olding
o clien p o eins (Hennessy e al., 2005). A linke egion connec s he DNA-J domain wi h he
cys eine s ing domain. The cys eine s ing domain is app oxima ely 25-amino-acids long and
con ains 13–15 cys eines, mos o hem palmi oyla ed. Palmi oyla ion is essen ial o a ge CSPα o
synap ic esicles and o p omo e neu o ansmi e elease (A nold e al., 2004). CSPαalso con ains
a C- e minal domain, he unc ion o which is no well-unde s ood.
Lopez-O ega e al. CSPαand Synap ic Main enance
FIGURE 1 | The lack/dec ease o CSPαinduces s uc u al and unc ional changes ha comp omise synap ic main enance. (A) Func ional domains o he
CSPαp o ein. (B) Synap ic elease de ec s (le ) and ac ion o mo o ne e e minals wi h mul ilamella bodies and acuoles in elec on mic oscopy p o iles ( igh ) s.
pos na al age in CSPαKO mice. G aphs summa ize nume ical alues in Ruiz e al. (2008, 2014) (le ) and in Fe nández-Chacon e al. (2004) ( igh ). (C) Two pa allel
chape one pa hways p omo e e icien SNARE complex o ma ion and no mal neu o ansmission by egula ing SNAP25, h ough CSPα(pa hway I), and
synap ob e in (VAMP2), h ough α-synuclein (pa hway II). The de ici in CSPαp oduces synap ic dys unc ion (Ruiz e al., 2008, 2014; Rozas e al., 2012), whose
se e i y, age o onse , and ime cou se depend on he amoun o unc ional CSPαa ailable. α-synuclein o e exp ession, howe e , can a oid he synap ic pa hology
p oduced by a de ec in pa hway I by inc easing he o ma ion o SNARE complexes (Sha ma e al., 2011, 2012a). (D) Hypo he ical model o how gene ic abla ion,
gene mu a ions, o inc eased CSPαdeg ada ion induce a posi i e loop o neu o ansmi e (NT) elease de ici , accumula ion o mis olded synap ic p o eins, and
neu odegene a ion. In humans, i emains unknown o wha ex en CSPαhaploinsu iciency, seques a ion o CSPαin agg ega es, and abe an palmi oyla ion o
CSPαand o he p o eins con ibu e o ANCL.
CSPαDEFICIENCY AND SYNAPTIC
DYSFUNCTION
CSPαis no essen ial o synap ogenesis, bu i is equi ed
o no mal neu o ansmission and neu onal main enance in
lies (Zinsmaie e al., 1994), wo ms (Kashyap e al., 2014),
mice (Fe nández-Chacon e al., 2004), and humans (Nosko á
e al., 2011). Dele ion o he CSPαgene in D osophila p oduces
an emb yonic semile hal pheno ype, and lies ha su i e
o adul hood p esen neu o ansmi e elease al e a ions and
empe a u e-sensi i e pa alysis. Synap ic de ec s in CSPα-null
(CSPαKO) mice s a ea ly a e bi h, and dea h occu s
be o e 3 mon hs o age. Bo h mo o and senso y neu ons a e
a ec ed by he lack o CSPα(Fe nández-Chacon e al., 2004;
Schmi z e al., 2006). In mo o ne e e minals, he i s sign
o unc ional al e a ion appea s a 2 weeks o age and consis s
o epea ed bu s s o high- equency spon aneous elease (Ruiz
e al., 2008) (Figu e 1B). Only 4 days la e , he e minal displays
mul iple unc ional al e a ions such as educed quan um con en ,
low elease p obabili y, inc eased sho - e m acili a ion du ing
epe i i e s imula ion, and educed calcium sensi i i y o he
sec e o y machine y (Ruiz e al., 2008, 2014). In addi ion, he
size o he eadily eleasable pool o synap ic esicles is dec eased
(Rozas e al., 2012; Ruiz e al., 2014).
CSPαAS A MOLECULAR CO-CHAPERONE
CSPαin e ac s wi h se e al p o eins ha pa icipa e in exo-
/endocy osis, including syn axin, synap o agmin, N- and P/Q-
ype calcium channels, and dynamin 1 ( o a e iew see
Bu goyne and Mo gan, 2015). The unc ional signi icance o
many o hese in e ac ions is no well es ablished. Howe e ,
F on ie s in Neu oscience | www. on ie sin.o g 2Feb ua y 2017 | Volume 11 | A icle 39
Lopez-O ega e al. CSPαand Synap ic Main enance
one o he bes -known unc ions o CSPαis i s ole as a co-
chape one (Chambe lain and Bu goyne, 2000; Zinsmaie , 2010;
Donnelie and B aun, 2014). CSPαin e ac s wi h Hsc70 and
oge he e old clien p o eins such as SNAP25 (Sha ma e al.,
2011, 2012a; Zhang e al., 2012). SNAP25 is equi ed o he
assembly o he SNARE (soluble N-e hylmaleimide-sensi i e
ac o a achmen ecep o ) complex, o med by synap ob e in,
syn axin, and SNAP25, which in u n is essen ial o exocy osis
and neu o ansmi e elease (Figu e 1C). In CSPαKO mice,
bo h SNAP25 and SNARE complex le els a e educed by hal
(Chand a e al., 2005).
CSPαAND NEURODEGENERATION
In CSPαKO mo o ne e e minals, hallma ks o degene a ion
(i.e., acuoles and mul ilamella bodies) appea e y ea ly
(Fe nández-Chacon e al., 2004), e en be o e he e oked
elease de ec s become appa en (Figu e 1B, le g aphs). The
degene a ion is mo e p ominen in cells wi h high elec ical
ac i i y, such as mo o neu ons, pho o ecep o s, and GABAe gic
neu ons (Fe nández-Chacon e al., 2004; Schmi z e al., 2006;
Ga cía-Junco-Clemen e e al., 2010), sugges ing ha high
synap ic ac i i y po en ia es degene a ion, which in u n may
inc ease he elease de ici (Figu e 1D).
A he molecula le el, i has been p oposed ha SNAP25
educ ion plays a majo ole in neu odegene a ion. This
hypo hesis is ein o ced by he ac ha SNAP25 o e exp ession
in CSPαKO mice p e en s neu odegene a ion (Sha ma e al.,
2012a). Ne e heless, SNAP25 he e ozygous mice, wi h 50% o
he p o ein, a e pheno ypically no mal and do no de elop
neu odegene a ion (Washbou ne e al., 2002), indica ing ha
solely educing unc ional SNAP25 is no su icien o p oduce
he pa hology. On he o he hand, mis olded SNAP25 could
ha e a dominan nega i e e ec o e he no mally olded
p o ein copies, o ubiqui ina ed SNAP25 molecules could
accumula e in he p o easome, in e e ing wi h i s no mal
unc ion. Su p isingly, howe e , he ac ha pha macological
inhibi ion o he p o easome inc eases SNAP25 and SNARE
complex le els, and, hence, imp o es synap ic unc ion in CSPα-
deple ed cells (Sha ma e al., 2012b), has challenged his las
hypo hesis.
Rema kably, neu odegene a ion in CSPαKO mice is
p e en ed when SNARE complexes a e inc eased by he
o e exp ession o α-synuclein (Sha ma e al., 2011, 2012a),
in spi e o he ac ha SNAP25 le els a e no es o ed and,
p esumably, he amoun o mis olded SNAP25 is no educed.
O e exp ession o he mu a ed o m o α-synuclein A53T in
CSPαKO mice es o es li e span and mo o unc ion as well
as wild- ype (WT) α-synuclein (Chand a e al., 2005). On he
o he hand, o e exp ession o A30P α-synuclein does no escue
su i al, bu can ansi o ily amelio a e he elease de ici and he
calcium sensi i i y de ec in mo o ne e e minals o CSPαKO
mice (Ruiz e al., 2014). The pa ial e ec o A30P α-synuclein
is likely due o i s limi ed abili y o inc ease he o ma ion o
SNARE complexes. These indings sugges ha wo pa allel
pa hways egula e SNARE complex o ma ion (Figu e 1C),
and aise he ques ion o how he neu odegene a ion p og am
is ac i a ed in he absence o CSPα. The molecula basis o
he neu odegene a ion is unknown, bu a possibili y is ha
neu odegene a ion is linked o he educed abili y o he synapse
o o m SNARE complexes and, he e o e, o he misma ch
be ween unc ional demands and e icien elease.
CSPαDEFICIENCY IN HUMANS
Neu onal Ce oid Lipo uscinosis (NCLs) cons i u e a
he e ogeneous g oup o inhe i ed neu odegene a i e diso de s
cha ac e ized by lysosomal accumula ion o au o luo escen
ce oid-lipo uscin agg ega es in neu ons and o he cell ypes.
The clinical symp oms o NCLs include seizu es, mo emen
diso de s, cogni i e de e io a ion, and p og essi e demen ia,
ollowed by a p ema u e dea h. The majo i y o NCL cases a ec
child en, and only 10% o o al cases a e in adul s.
In ecen yea s, wo mu a ions in he gene ha encodes
CSPα,DNAJC5, ha e been linked o he de elopmen o adul -
onse NCL (ANCL) (MIM #162350). These mu a ions consis
o a poin mu a ion (p.L115R) and an in- ame codon dele ion
(p.L1161), bo h a ec ing dileucine esidues loca ed in he
cys eine s ing domain o CSPα(Nosko á e al., 2011). This
domain is highly palmi oyla ed and media es he memb ane
binding and in acellula a ge ing o CSPα. The e o e, mu a ions
in his egion may explain he di use in acellula localiza ion
o CSPαobse ed in he neu ons o ANCL pa ien s. Mo eo e ,
he mu a ed o ms o CSPαp esen an inc eased endency
o sel -associa e, o ming de e gen - esis an agg ega es. These
agg ega es in e e e wi h WT CSPαp o eins, educing he co-
chape one unc ion o CSPαin neu ons (Nosko á e al., 2011;
G ea es e al., 2012; Zhang and Chand a, 2014) (Figu e 1D),
which is likely one o he main easons why he NCL-linked
DNAJC5 gene mu a ions display an au osomal dominan (AD)
inhe i ance pa e n. Addi ionally, a dominan e ec o mu a ed
CSPαon he palmi oyla ion pa e n o lysosomal and synap ic
p o eins has been sugges ed as a mechanism o he de elopmen
o DNAJC5-linked ANCL (Hende son e al., 2016).
LONG-TERM MODERATE CSPα
DEFICIENCY ALTERS MOTOR
RESPONSES
In e es ingly, only homozygous CSPαKO mice p esen synap ic
de ec s, while he e ozygous mu an mice appea pheno ypically
no mal up o 3 mon hs o age (Fe nández-Chacon e al., 2004).
Gi en he la e onse o AD-ANCL (a ound 30 yea s o age),
we s udied he mo o unc ion o 1-yea -old CSPαhe e ozygous
mice. Mo o pe o mance was i s assessed wi h Balance and
G ip S eng h es s (Figu e 2A). The balance was measu ed by
placing he mouse on a ho izon al pole suspended in he ai .
The pole was o a ed manually a a cons an speed o one
o a ion cycle pe second (Figu e 2A le ). The g ip s eng h
es consis ed o suspending he mouse om he pole by i s
o elimbs (Figu e 2A igh ). In bo h ials, he amoun o ime
he mouse emained suspended om he pole (maximum 10 s)
F on ie s in Neu oscience | www. on ie sin.o g 3Feb ua y 2017 | Volume 11 | A icle 39
Lopez-O ega e al. CSPαand Synap ic Main enance
FIGURE 2 | The neu omuscula unc ion o 1-yea -old CSPαhe e ozygous mice is al e ed. (A,B) Balance and g ip s eng h es s show no signi ican
di e ences be ween CSPαhe e ozygous (n=27) and WT mice (n=9). The plo illus a es he a e age alues ob ained in h ee eplica es/session o each geno ype
(Mann-Whi ney U es ). (C) Rep esen a i e eco dings o CMAPs in a CSPα+/+mouse a e sup amaximal s imula ion o he scia ic ne e (1s and 15 h esponses a
di e en s imula ion equencies). (D) Dep ession o he neu omuscula esponses (CMAP no malized ampli ude) is signi ican ly la ge in CSPα+/−(n=25) han in WT
mice (n=7) du ing s imula ion ains a 20, 50, and 100 Hz. (E) Maximal dep ession o he neu omuscula esponse (no malized) a di e en s imula ion equencies in
CSPα+/−(n=24–25) and WT mice (n=7) (Mann-Whi ney U es ). Ei he sex expe imen al mice (C57BL/6 backg ound) we e used. The mouse line was kindly
dona ed by D . Südho . All expe imen s we e pe o med acco ding o he guidelines o he Eu opean Council Di ec i e o he Ca e o Labo a o y Animals. The
p o ocol was app o ed by he E hics Commi ee o Animal Expe imen a ion o he Jun a de Andalucía ( e . 23-11-2015-364).
was measu ed. Two sessions sepa a ed by 1 week we e pe o med
o each es (Figu e 2B). Da a ob ained om he neu ological
es s showed no signi ican di e ences be ween WT and CSPα
he e ozygous mice, in ei he balance o g ip s eng h.
Nex , he neu omuscula esponse o CSPαhe e ozygous mice
was s udied using elec omyog aphy (EMG). E oked Compound
Mo o Ac ion Po en ials (CMAPs) we e eco ded om he igh
la e al gas ocnemius o anes he ized mice. S imula ion needle
elec odes we e placed a he scia ic no ch and he head o he
ibula (Ruiz e al., 2005). The ac i e eco ding elec ode was
placed in he medial egion o he eco ded muscle. The e e ence
elec ode was inse ed a he base o he i h oo phalanx.
The g ound elec ode was loca ed a he base o he ail. B ie
sup amaximal s imula ion pulses we e applied a 10 Hz (2 s),
20 Hz (1 s), 50 Hz (1 s), and 100 Hz (0.5 s). Rep esen a i e
eco dings o CMAPs egis e ed du ing he ains a e shown
in Figu e 2C. The s udy e ealed enhanced dep ession wi h
s imula ions be ween 20 and 100 Hz in CSPαhe e ozygous mice
compa ed o WT li e ma es (Figu e 2D). The mean maximal
dep ession was 5% (20 Hz), 12% (50 Hz), and 25% (100 Hz) lowe
in CSPαhe e ozygous han in WT mice, while no signi ican
di e ence was obse ed a 10 Hz (Figu e 2E). Rema kably, he
dep ession in he EMG eco dings was simila o ha seen in
3-week-old CSPαKO mice (Fe nández-Chacon e al., 2004), a
pheno ype no obse ed in CSPα+/−mice up o 3 mon h o age.
These esul s indica e ha , o e ime, a mode a e educ ion o
CSPαexp ession al e s he abili y o he neu omuscula sys em
o espond no mally o s imula ion.
FUTURE DIRECTIONS
The mul iple unc ions o CSPα ange om ac ing as a
chape one, pa icipa ing in he assembly and dissocia ion o
mul i-p o ein complexes, and egula ing Ca2+sensi i i y o
neu o ansmi e elease. The se e e unc ional and s uc u al
changes ha ake place in he absence o CSPαin in e eb a e
and e eb a e o ganism models con i m he impo ance o
his p o ein in synapse main enance and neu o ansmi e
elease. In humans, CSPαmu a ions a e associa ed wi h he
de elopmen o AD-ANCL, synap ic degene a ion, and neu onal
F on ie s in Neu oscience | www. on ie sin.o g 4Feb ua y 2017 | Volume 11 | A icle 39
Lopez-O ega e al. CSPαand Synap ic Main enance
loss. The e o e, al hough bo h he educ ion o CSPαexp ession
and he p esence o CSPαmu a ions a e pa hogenic o he
synapse, he se e i y and ime cou se o he neu ological
impai men s may a y om se e e, including p ema u e dea h,
o mild, depending on he amoun o unc ional CSPαin each
case. The mode a e dec ease in CSPαand SNARE complexes in
neu ons o e ime could esul in mo o unc ion impai men
and, in addi ion, in luence he e olu ion o common age-
ela ed neu odegene a i e diso de s, such as Alzheime ’s and
Pa kinson’s diseases. Fu u e challenges a e o iden i y pa ien s
wi h educed le els o molecula chape ones (such as CSPα),
deciphe he mechanisms esponsible o he molecula de ici ,
unde s and how he homeos asis o he synapse is al e ed, and
de e mine o wha ex en he educ ion o he chape ones
in luences he se e i y o associa ed neu odegene a i e
diseases.
AUTHOR CONTRIBUTIONS
Expe imen s shown in Figu e 2 we e pe o med by EL. EL, RR,
and LT concei ed and w o e he manusc ip .
FUNDING
This wo k was suppo ed by g an s om he Spanish Minis y
o Science and Inno a ion (BFU2013–43763-P) and he Ta iana
Pe ez de Guzman Founda ion o LT. RR was suppo ed by a
con ac om he V Plan P opio o he Uni e si y o Se ille.
ACKNOWLEDGMENTS
We a e g a e ul o Ra ael Fe nández-Chacón o discussions and
commen s on he manusc ip .
REFERENCES
A nold, C., Reisch, N., Leibold, C., Becke , S., P u e , K., Sau e , K., e al.
(2004). S uc u e- unc ion analysis o he cys eine s ing p o ein in D osophila:
cys eine s ing, linke and C e minus. J. Exp. Biol. 207, 1323–1334.
doi: 10.1242/jeb.00898
B aun, J. E., Wilbanks, S. M., and Schelle , R. H. (1996). The cys eine
s ing sec e o y esicle p o ein ac i a es Hsc70 ATPase. J. Biol. Chem. 271,
25989–25993. doi: 10.1074/jbc.271.42.25989
Bu goyne, R. D., and Mo gan, A. (2015). Cys eine s ing p o ein (CSP) and i s
ole in p e en ing neu odegene a ion. Semin. Cell De . Biol. 40, 153–159.
doi: 10.1016/j.semcdb.2015.03.008
Chambe lain, L. H., and Bu goyne, R. D. (2000). Cys eine-s ing
p o ein: he chape one a he synapse. J. Neu ochem. 74, 1781–1789.
doi: 10.1046/j.1471-4159.2000.0741781.x
Chand a, S., Galla do, G., Fe nandez-Chacon, R., Schlu e , O. M., and Sudho , T.
C. (2005). α-synuclein coope a es wi h CSPαin p e en ing neu odegene a ion.
Cell 123, 383–396. doi: 10.1016/j.cell.2005.09.028
Donnelie , J., and B aun, J. E. (2014). CSPα-chape oning p esynap ic p o eins.
F on . Cell. Neu osci. 8:116. doi: 10.3389/ ncel.2014.00116
Fe nández-Chacon, R., Wol el, M., Nishimune, H., Taba es, L., Schmi z,
F., Cas ellano-Munoz, M., e al. (2004). The synap ic esicle p o ein
CSPαp e en s p esynap ic degene a ion. Neu on 42, 237–251.
doi: 10.1016/S0896-6273(04)00190-4
Ga cía-Junco-Clemen e, P., Can e o, G., Gomez-Sanchez, L., Lina es-Clemen e,
P., Ma inez-Lopez, J. A., Lujan, R., e al. (2010). Cys eine s ing p o ein-α
p e en s ac i i y-dependen degene a ion in GABAe gic synapses. J. Neu osci.
30, 7377–7391. doi: 10.1523/JNEUROSCI.0924-10.2010
G ea es, J., Lemonidis, K., Go leku, O. A., C uchaga, C., G e en, C., and
Chambe lain, L. H. (2012). Palmi oyla ion-induced agg ega ion o cys eine-
s ing p o ein mu an s ha cause neu onal ce oid lipo uscinosis. J. Biol. Chem.
287, 37330–37339. doi: 10.1074/jbc.M112.389098
Hende son, M. X., Wi ak, G. S., Zhang, Y. Q., Dai, F., Ginsbe g, S.
D., Dolzhanskaya, N., e al. (2016). Neu onal ce oid lipo uscinosis
wi h DNAJC5/CSPαmu a ion has PPT1 pa hology and exhibi
abe an p o ein palmi oyla ion. Ac a Neu opa hol. 131, 621–637.
doi: 10.1007/s00401-015-1512-2
Hennessy, F., Nicoll, W. S., Zimme mann, R., Chee ham, M. E., and Bla ch, G.
L. (2005). No all J domains a e c ea ed equal: implica ions o he speci ici y
o Hsp40-Hsp70 in e ac ions. P o . Sci. 14, 1697–1709. doi: 10.1110/ps.0514
06805
Kashyap, S. S., Johnson, J. R., McCue, H. V., Chen, X., Edmonds, M. J., Ayala, M.,
e al. (2014). Caeno habdi is elegans dnj-14, he o hologue o he DNAJC5 gene
mu a ed in adul onse neu onal ce oid lipo uscinosis, p o ides a new pla o m
o neu op o ec i e d ug sc eening and iden i ies a SIR-2.1-independen
ac ion o es e a ol. Hum. Mol. Gene . 23, 5916–5927. doi: 10.1093/hmg/
ddu316
Nosko á, L., S anecky, V., Ha manno a, H., P is oupilo a, A., Ba eso a,
V., I anek, R., e al. (2011). Mu a ions in DNAJC5, encoding cys eine-
s ing p o ein alpha, cause au osomal-dominan adul -onse neu onal ce oid
lipo uscinosis. Am. J. Hum. Gene . 89, 241–252. doi: 10.1016/j.ajhg.2011.
07.003
Rozas, J. L., Gomez-Sanchez, L., Mi cheski, J., Lina es-Clemen e, P., Nie o-
Gonzalez, J. L., Vazquez, M. E., e al. (2012). Mo o neu ons equi e cys eine
s ing p o ein-α o main ain he eadily eleasable esicula pool and synap ic
esicle ecycling. Neu on 74, 151–165. doi: 10.1016/j.neu on.2012.02.019
Ruiz, R., Biea, I. A., and Taba es, L. (2014). α-Synuclein A30P
dec eases neu odegene a ion and inc eases synap ic esicle elease
p obabili y in CSPα-null mice. Neu opha macology 76(P A), 106–117.
doi: 10.1016/j.neu opha m.2013.08.032
Ruiz, R., Casanas, J. J., Sudho , T. C., and Taba es, L. (2008). Cys eine
s ing p o ein-αis essen ial o he high calcium sensi i i y o
exocy osis in a e eb a e synapse. Eu . J. Neu osci. 27, 3118–3131.
doi: 10.1111/j.1460-9568.2008.06301.x
Ruiz, R., Lin, J., Fo gie, A., Fole i, D., Shel on, D., Rosen hal, A., e al.
(2005). T ea men wi h kC agonis an ibodies delays disease p og ession in
neu omuscula degene a ion (NMD) mice. Hum. Mol. Gene . 14, 1825–1837.
doi: 10.1093/hmg/ddi189
Schmi z, F., Taba es, L., Khimich, D., S enzke, N., de la Villa-Polo, P.,
Cas ellano-Munoz, M., e al. (2006). CSPα-de iciency causes massi e and apid
pho o ecep o degene a ion. P oc. Na l. Acad. Sci. U.S.A. 103, 2926–2931.
doi: 10.1073/pnas.0510060103
Sha ma, M., Bu e, J., B onk, P., Zhang, Y., Xu, W., and Sudho , T. C. (2012a).
CSPαknockou causes neu odegene a ion by impai ing SNAP-25 unc ion.
EMBO J. 31, 829–841. doi: 10.1038/emboj.2011.467
Sha ma, M., Bu e, J., and Sudho , T. C. (2011). CSPαp omo es SNARE-complex
assembly by chape oning SNAP-25 du ing synap ic ac i i y. Na . Cell Biol. 13,
30–39. doi: 10.1038/ncb2131
Sha ma, M., Bu e, J., and Sudho , T. C. (2012b). P o easome inhibi ion
alle ia es SNARE-dependen neu odegene a ion. Sci. T ansl. Med. 4:147 a113.
doi: 10.1126/sci anslmed.3004028
Washbou ne, P., Thompson, P. M., Ca a, M., Cos a, E. T., Ma hews, J. R.,
Lopez-Bendi o, G., e al. (2002). Gene ic abla ion o he -SNARE SNAP-
25 dis inguishes mechanisms o neu oexocy osis. Na . Neu osci. 5, 19–26.
doi: 10.1038/nn783
Zhang, Y. Q., and Chand a, S. S. (2014). Oligome iza ion o Cys eine S ing P o ein
alpha mu an s causing adul neu onal ce oid lipo uscinosis. Biochim. Biophys.
Ac a 1842, 2136–2146. doi: 10.1016/j.bbadis.2014.07.009
Zhang, Y. Q., Hende son, M. X., Colangelo, C. M., Ginsbe g, S. D., B uce,
C., Wu, T., e al. (2012). Iden i ica ion o CSPαclien s e eals a ole
F on ie s in Neu oscience | www. on ie sin.o g 5Feb ua y 2017 | Volume 11 | A icle 39

Lopez-O ega e al. CSPαand Synap ic Main enance
in dynamin 1 egula ion. Neu on 74, 136–150. doi: 10.1016/j.neu on.2012.
01.029
Zinsmaie , K. E. (2010). Cys eine-s ing p o ein’s neu op o ec i e ole. J.
Neu ogene . 24, 120–132. doi: 10.3109/01677063.2010.489625
Zinsmaie , K. E., Ebe le, K. K., Buchne , E., Wal e , N., and Benze , S. (1994).
Pa alysis and ea ly dea h in cys eine s ing p o ein mu an s o D osophila.
Science 263, 977–980. doi: 10.1126/science.8310297
Zinsmaie , K. E., Ho baue , A., Heimbeck, G., P lug elde , G. O., Buchne , S., and
Buchne , E. (1990). A cys eine-s ing p o ein is exp essed in e ina and b ain o
D osophila. J. Neu ogene . 7, 15–29. doi: 10.3109/01677069009084150
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