F on ie s in Neu oana omy 01 on ie sin.o g
Del Río Ho ega’s insigh s in o
oligodend ocy es: ecen
ad ances in sub ype
cha ac e iza ion and unc ional
oles in axonal suppo and
disease
Ene i zLópez-Mugu uza
1,2,3, Ca laPei ó-Mo eno
1,2,3,
Fe nandoPé ez-Ce dá
1,3,4, Ca losMa u e
1,3,4* and Asie Ruiz
1,3,4*
1 Depa men o Neu osciences, Uni e si y o he Basque Coun y UPV/EHU, Leioa, Spain, 2 Achuca o
Basque Cen e o Neu oscience, Leioa, Spain, 3 CIBERNED-Ins i u o de Salud Ca los III, Leioa, Spain,
4 Depa men o Neu osciences, Biobizkaia, Ba akaldo, Spain
Pío Del Río Ho ega (1882–1945) was a gian o mode n neu oscience and pe haps
he mos impac ul membe o Cajal’s School. His con ibu ions o cla i ying he
s uc u e o he ne ous sys em we e key o unde s anding he b ain beyond neu ons.
Heunco e ed mic oglia and oligodend ocy es, he la e un il hen named mesoglia.
Mos impo an ly, he cha ac e iza ion o oligodend oglia sub ypes hemade has
s ood he omics e olu ion ha added molecula de ails ele an o comp ehend
hei biological p ope ies. As ounding as i may seem on oday’s eyes, hepos ula ed
a cen u y ago ha oligodend ocy es p o ide ophic suppo o axons, an idea
ha is now beyond doub and unde sc u iny as dys unc ion a he axon-myelin
uni is key o neu odegene a ion. He e, we e ised ecen key ad ancemen s in
oligodend ocy e biology ha shed ligh on Ho ega’s ideas a cen u y ago.
KEYWORDS
oligodend ocy e, myelin, axon, me abolism, disease
1 In oduc ion: Pío Del Río Ho ega’s legacy and he
me abolic oles o oligodend ocy es
Pío del Río-Ho ega (1882–1945) was one o he mos p ominen igu es in he Spanish
school o neu ology (Boulle ne and Feins ein, 2020; De Cas o, 2019; Del Río-Ho ega
Be ecia u, 2020; Pé ez-Ce dá e al., 2015). Men o ed by he excep ional neu ohis opa hologis
Nicolás Achúca o, hesucceeded him as he head o he “Labo a o y o Neu opa hology,” a
di ision o Cajal’s labo a o y. The e, he e olu ionized he s udy o glial cells by disco e ing
mic oglia and oligodend ocy es (OLs) h ough inno a i e modi ica ions o sil e s aining
echniques (Río-Ho ega, 1917). Fo he i s ime, his me hod success ully s ained dis inc
cy oplasmic p ojec ions in apola cells, p e iously classi ied as he “ hi d elemen .” Heiden i ied
wo dis inc cell ypes and cla i ied hei o igins: mic oglia, he ue “ hi d elemen ” due o i s
mesode mal o igin, and he “in e ascicula glia,” cha ac e ized by e y ew p ocesses, which
heg ouped wi h as ocy es as pa o he “second elemen ” due o hei sha ed ec ode mal
o igin (Río-Ho ega, 1920). Sho ly a e , hecoined he e m “oligodend oglia” (oligo = ew;
dend o = b anches) o in e ascicula glia, as hese cells we e ound no only in whi e ma e
bu also di usely dis ibu ed h oughou he Cen al Ne ous Sys em (CNS), o en clus e ed
nea neu ons (Río-Ho ega, 1921).
OPEN ACCESS
EDITED BY
Fe nando de Cas o,
Spanish Na ional Resea ch Council (CSIC),
Spain
REVIEWED BY
Juan M. Espinosa-Sanchez,
Hospi al Uni e si a io Vi gen de las Nie es,
Spain
Rogelio O. A ellano,
Ins i u o de Neu obiologia Uni e sidad
Nacional Au onoma de Mexico, Mexico
Ca men Sa o-Bigbee,
Vi ginia Commonweal h Uni e si y,
Uni edS a es
*CORRESPONDENCE
Asie Ruiz
asie [email p o ec ed]
Ca los Ma u e
[email p o ec ed]
RECEIVED 08 Janua y 2025
ACCEPTED 25 Feb ua y 2025
PUBLISHED 12 Ma ch 2025
CITATION
López-Mugu uza E, Pei ó-Mo eno C,
Pé ez-Ce dá F, Ma u e C and Ruiz A (2025)
Del Río Ho ega’s insigh s in o
oligodend ocy es: ecen ad ances in sub ype
cha ac e iza ion and unc ional oles in
axonal suppo and disease.
F on . Neu oana . 19:1557214.
doi: 10.3389/ nana.2025.1557214
COPYRIGHT
© 2025 López-Mugu uza, Pei ó-Mo eno,
Pé ez-Ce dá, Ma u e and Ruiz. This is an
open-access a icle dis ibu ed unde he
e ms o he C ea i e Commons A ibu ion
License (CC BY). The use, dis ibu ion o
ep oduc ion in o he o ums is pe mi ed,
p o ided he o iginal au ho (s) and he
copy igh owne (s) a e c edi ed and ha he
o iginal publica ion in his jou nal is ci ed, in
acco dance wi h accep ed academic
p ac ice. No use, dis ibu ion o ep oduc ion
is pe mi ed which does no comply wi h
hese e ms.
TYPE Re iew
PUBLISHED 12 Ma ch 2025
DOI 10.3389/ nana.2025.1557214
López-Mugu uza e al. 10.3389/ nana.2025.1557214
F on ie s in Neu oana omy 02 on ie sin.o g
His indings on mic oglial s uc u e, i s su eillance unc ion,
and i s phagocy ic capaci y we e ela i ely quickly accep ed by he
scien i ic communi y, al hough he mesode mal o igin o
mic oglia emained a subjec o con o e sy. In con as , his
disco e y o oligodend oglia aced skep icism om his
con empo a ies, delaying i s accep ance and ul ima ely
con ibu ing o his dismissal om Cajal’s labo a o y. Unde e ed,
del Río-Ho ega es ablished his own labo a o y, whe e
hemen o ed se e al dis inguished scien is s, including Wilde
Pen ield. Th oughou he 1920s, heconduc ed ex ensi e esea ch
on his newly iden i ied cell ype. In 1928, he published a
comp ehensi e monog aph de ailing he mo phology and unc ion
o oligodend oglia (Río-Ho ega, 1928). By his ime, he had
de eloped a new me al imp egna ion p o ocol based on he Golgi
me hod, known as he Golgi-Ho ega echnique, which p o ided
unp eceden ed mo phological de ail. Heclassi ied OLs in o h ee
ypes based on hei spa ial ela ionships: in e ascicula OLs
(aligned in ows along axonal ac s), pe ineu onal OLs (closely
associa ed wi h neu onal soma a), and pe i ascula OLs (adjacen
o blood essels bu lacking di ec con ac ). Del Río-Ho ega was
ascina ed by he in icacy, ichness, and di e si y o
oligodend ocy ic mo phology. Based on a ia ions in soma size
and shape, he numbe and o ien a ion o cellula p ocesses, hei
dis ibu ion wi hin he CNS, hei in e ac ions wi h axons, and he
size o indi idual axons, he u he ca ego ized OLs in o ou
sub ypes, while acknowledging he absence o s ic bounda ies
be ween hem.
This classi ica ion was no me ely desc ip i e; del Río-Ho ega
also in eg a ed mo phological and physiological insigh s in o
oligodend oglia, laying he ounda ion o he concep o neu oglioma
(Río-Ho ega, 1942). He p oposed ha OLs main ain a close
associa ion wi h neu ons and hypo hesized ha hey se e mechanical,
ophic, and myelinogenic unc ions. Th oughou his ca ee ,
hega he ed subs an ial e idence suppo ing he ole o OLs in myelin
o ma ion, ei he di ec ly o by supplying axons wi h essen ial
ma e ials. Howe e , he emained cau ious in d awing de ini i e
conclusions—a con i ma ion ha ul ima ely came wi h he ad en o
elec on mic oscopy in he 1960s. This empo al gap, along wi h he
limi a ions o oligodend oglia s aining echniques p io o he
in oduc ion o immunohis ochemis y, con ibu ed o he unde
app ecia ion o his wo k. Addi ionally, many o his seminal
publica ions we e w i en in Spanish (Iglesias-Rozas and Ga osa,
2012), u he limi ing hei in e na ional ecogni ion compa ed o his
disco e y o mic oglia. Despi e hese challenges, del Río-Ho ega was
wice nomina ed o he Nobel P ize. Howe e , hewas ne e awa ded
he hono , la gely due o ex insic ac o s such as he hos ili y and en y
o ce ain conse a i e Spanish academics, as well as he poli ical
clima e o he ime—he spen he inal yea s o his li e in exile (Del
Río-Ho ega Be ecia u, 2020).
The OL pheno ypic di e si y p oposed by del Río-Ho ega was
ini ially neglec ed, and con i med la e wi h obse a ions a ising om
di e en egions o g ay and whi e ma e , ul as uc u al analysis by
elec on mic oscopy, in acellula dye injec ion, size and shape
mo phome ic analysis as well as elec ophysiology s udies and
molecula ma ke s (Lassmann, 2012; Bu , 2013; an B uggen e al.,
2017; Edga e al., 2021). In addi ion, ecen e idence abou axonal
me abolic suppo p o ided by OLs (Asadollahi e al., 2024) ela es o
he concep o neu ogliona sugges ed by Río-Ho ega (1942).
2 Mode n cha ac e iza ion o
oligodend ocy es: a molecula
pe spec i e
The las decade has wi nessed an eno mous ad ance in he
cha ac e iza ion o oligodend oglia. I is now well es ablished ha OL
popula ions also a y in he way hey gene a e myelin in e ms o
in e nodal leng h and shea h hickness (Bechle e al., 2015) and ha OL
p ogeni o s di e in hei p ope ies du ing de elopmen and in he
ma u e CNS (C aw o d e al., 2016). Mos no ably, ansc ip omics has
unco e ed dis inc gene exp ession p o iles and unc ional cha ac e is ics
o hese sub ypes, highligh ing hei di e se me abolic unc ions and
in e ac ions wi h neu ons. In his sec ion, we ocus on he classi ica ion
a ising om ansc ip ome analysis and speci y new ea u es ecen ly
unco e ed o bo h pe i ascula and disease-associa ed oligodend oglia.
2.1 T ansc ip ome analysis un eiled
unexpec edly di e se oligodend ocy e
sub ypes wi h dis inc molecula signa u es
Mic oa ay analysis p o ided a deepe insigh in o oligodend oglia
di e si y. Thus, Ba es and colleagues p o ided he i s glimpse o he
di e en and complex ansc ip omic signa u es o mouse OL
p ogeni o s as well as newly- o med and myelina ing OL om
di e en a eas (Cahoy e al., 2008; Zhang e al., 2014). Subsequen ly,
mic oa ay s udies cla i ied he exp ession p o iles o OL p ogeni o s
in demyelina ion and emyelina ion (Moyon e al., 2015).
Al hough mic oa ay and bulk RNA sequencing p o ided
subs an ial in o ma ion abou oligodend oglia sub ypes, hey lacked
single cell and spa ial esolu ion. Indeed, i was wi h he in oduc ion
o single cell/nuclei RNA sequencing ha weha e d as ically e ined
ou unde s anding o OL sub ypes and e ealed hei he e ogenei y
and new speci ic oles in he CNS (Ma ques e al., 2016; Weng e al.,
2025; Zeisel e al., 2015). In his ega d, he pionee ing wo k by
Cas elo-B anco’s labo a o y has been enligh ening and highly
cla i ying (Cas elo-B anco e al., 2024; an B uggen e al., 2017).
Single-cell RNA sequencing o he OL lineage in he mouse ju enile
and adul CNS iden i ied wel e dis inc popula ions o OLs which
ep esen a con inuum om PDGFRα (+) OL p ecu so cells (OPCs)
o dis inc ma u e OLs (Ma ques e al., 2016) (Figu e1). This s udy also
un eiled a second PDGFRα (+) popula ion, dis inc om OPCs, loca ed
along blood essels. In e es ingly, newly o med OLs in he adul CNS
espond o complex mo o lea ning. These apidly myelina ing OLs may
also pa icipa e in emyelina ion in disease. Newly o med OLs a e
cha ac e ized by he exp ession o inosi ol 1,4,5- isphospha e ecep o
ype 2 (ITPR2), an endoplasmic e iculum calcium channel, e ealing
he key ole o calcium homeos asis in oligodend oglia ma u a ion
(Zeisel e al., 2015). The main de e minan s o he dis inc molecula
signa u es in each oligodend ocy e sub ype and hei unc ional
co ela es a e desc ibed in de ail in he e e ences in his sec ion.
2.2 Pe i ascula oligodend oglia con ibu e
o he mic o ascula u e en i onmen
Del Río-Ho ega’s i s desc ip ion o oligodend oglia pos ula ed a
possible unc ional connec ion be ween ma u e OLs and he ascula u e
López-Mugu uza e al. 10.3389/ nana.2025.1557214
F on ie s in Neu oana omy 03 on ie sin.o g
(Río-Ho ega, 1928). Indeed, OPCs mig a e along blood essels du ing
de elopmen and epai while exchanging signals ha p omo e
di e en ia ion and su i al as well as s imula ing angiogenesis (Tsai e al.,
2016). A he same ime, hey con ibu e o blood–b ain ba ie (BBB)
in eg i y p omo ing igh -junc ion p o ein exp ession in endo helial cells
(Seo e al., 2014). Likewise, he la e a ou myelin o ma ion by ma u e
OLs (Swi e e al., 2019) ha in u n elease me allop o einases
con ibu ing o ascula emodelling. These in e ac ions appea o occu
h oughou he CNS as hey ake place in hippocampus, ce eb al co ex
and o e all, in whi e and g ay ma e ac oss di e en species. Speci ically,
a ound a i h o ma u e OLs con ac wi h capilla ies, a e ioles and
enules in he ce eb al co ex, hippocampus and ce ebella co ex (Palhol
e al., 2023). This in ima e in e ac ion in ol es di ec connec ion wi h he
ascula basemen memb ane and possibly me aboli e exchange wi h
endo helial cells ha may a ou epai mechanisms du ing emyelina ion
(Palhol e al., 2023). The e o e, pe i ascula oligodend oglia may indeed
bean in eg al pa o he ascula u e mic oen i onmen and con ibu es
o he p ope ies o he BBB.
2.3 Disease-associa ed oligodend oglia:
b idging he gap be ween in lamma ion
and neu odegene a ion
Single-cell/nuclei RNA sequencing and spa ial ansc ip omics
e ealed disease-associa ed s a es o mic oglia and as ocy es changing
he classical iew o hese cell ypes o me ely wo al e na i e s a es in
heal h and disease espec i ely, o a mo e elabo a ed iew in which
bo h cell ypes unde go a g adien o ansi ional s ages (Esca in
e al., 2021; Paolicelli e al., 2022). Unexpec edly, eme ging da a
indica es ha oligodend oglia may also expe ience g adual changes
du ing in lamma ion in mul iple scle osis (MS) (Falcão e al., 2018).
Indeed, one could e m hose s a es as in lamma o y OLs opening he
ga e o he idea ha hese cells may become immunocompe en unde
ce ain condi ions (e.g., encephalomyeli is and upon IFN-γ exposu e)
as hey may exp ess MHC-I and–II genes and hus, con ibu e o
neu oin lamma ion and neu odegene a ion (Cas elo-B anco e al.,
2024; Ki by and Cas elo-B anco, 2021).
This no el idea p o ides solid e idence ha oligodend oglia, in
addi ion o hei myelina ing p ope ies, ha e he po en ial o
ansi ion o disease-associa ed s a es, cha ac e ized by he exp ession
o immune genes in he in lamed CNS (Cas elo-B anco e al., 2024).
Thus, in lamma o y cy okines sec e ed du ing in lamma ion may
d i e sec e ion o chemokines and exp ession o MHC-I in OL
p ogeni o s ha migh p opaga e he immune esponse. The a e o
ac i a ed p ogeni o s is unclea . E idence sugges s al e na i e
possibili ies including cell dea h ia caspase 3/7 up egula ion, su i al
main aining hei disease-associa ed s a e, o e u n in o homeos a ic
p ogeni o s o p omo e emyelina ion. In addi ion, in lamma ion can
also u n ma u e OLs in o a disease s age along wi h MHC-I/II
exp ession using simila mechanisms o hose in p ogeni o s
(Figu e2).
3 Oligodend ocy e me abolism and
axonal suppo
OLs, adi ionally ecognized as he p ima y a chi ec s o myelin
in he CNS, a e now also acknowledged o hei ole in sus aining
axonal heal h h ough me abolic suppo (Baumann and Pham-Dinh,
2001). While hei con ibu ion o o ming and main aining he
myelin shea h o axonal insula ion has been unde s ood since he
ea ly 1920s, suppo ed by nume ous s udies and elec on mic oscopy
echniques (Bunge e al., 1962; Río-Ho ega, 1928; Doyle, 1978), hei
unc ions ex end beyond his s uc u al ole. In addi ion o acili a ing
sal a o y conduc ion o e icien ne e impulse ansmission, OLs a e
essen ial componen s o a b oade glial ne wo k ha p o ides
me abolic suppo and egula es he neu onal en i onmen h ough
ion and wa e homeos asis (Na e, 2010; S adelmann e al., 2019). This
ion balance is egula ed by channels loca ed a he junc ion o he
myelin shea h and he axon (Suminai e e al., 2019). As a key signalling
molecule and second messenge , he egula ion o in acellula
calcium concen a ion ([Ca
2+
]
i
) in OLs, including speci ic egions
wi hin he myelin shea h, plays a c ucial ole in myelin o ma ion and
emodelling. I may also a ec o he unc ions ha a e ye o be ully
unco e ed (Paez and Lyons, 2020). Building on his unde s anding o
FIGURE1
Cu en iew o oligodend oglia he e ogenei y. OPC, oligodend ocy e p ecu so cell; COP, commi ed oligodend ocy e p ogeni o s; NFOL, newly
o med oligodend ocy e; MFOL, myelin- o ming oligodend ocy e; MOL, ma u e oligodend ocy e. Adap ed om an B uggen e al. (2017).
López-Mugu uza e al. 10.3389/ nana.2025.1557214
F on ie s in Neu oana omy 04 on ie sin.o g
OL unc ions is essen ial o examine how hese cells mee hei high-
ene gy demands h ough speci ic me abolic p ocesses.
3.1 Me abolic pa hways in
oligodend ocy es: glucose, lac a e, and
ke ones
Glucose me abolism plays a c i ical ole in he CNS, se ing as he
p ima y ene gy sou ce o b ain cells and suppo ing i al unc ions
such as ATP p oduc ion, neu o ansmi e syn hesis, and oxida i e
s ess egula ion (Me gen hale e al., 2013). The b ain gene a es ATP
mainly h ough wo me abolic pa hways: glycolysis, which occu s in
he cy osol, and oxida i e phospho yla ion (OXPHOS) in he
mi ochond ia (Dienel, 2019). In compa ison o glycolysis, OXPHOS
p oduces mo e ATP due o he in ol emen o he ci ic acid cycle
(TCA). Al hough he TCA cycle i sel does no p oduce signi ican
ATP, i p o ides elec ons o he elec on anspo chain (ETC). The
ETC hen gene a es a mi ochond ial memb ane po en ial ha d i es
ATP p oduc ion h ough OXPHOS, wi h oxygen se ing as he inal
elec on accep o (A nold and Finley, 2023; Bono a e al., 2012).
Despi e hei high-ene gy demands, due o in ol emen in ene gy-
in ensi e unc ions such as myelin main enance, p o ein and lipid
syn hesis, and cy oskele on emodelling, OLs exhibi a p e e ence o
glycolysis o e OXPHOS o mee hei ATP needs (Na ine and Cologna o,
2022) (Figu e2). This eliance on glycolysis no only suppo s hei ene gy
needs bu also enables hem o unc ion e icien ly in he low-oxygen
en i onmen o he whi e ma e , whe e OLs a e p esen in signi ican
numbe s. Mo eo e , ma u e OLs can me abolize glucose in he cy osol
and py u a e in mi ochond ia (Ama al e al., 2016). The ansi ion o
glycolysis ollowing de elopmen al myelina ion indica es ha OLs adop
a s a egy o dec easing eliance on mi ochond ial ene gy me abolism o
suppo myelin main enance and axonal in eg i y (Fün schilling e al.,
2012). This shi om OXPHOS o glycolysis may help minimize he
p oduc ion o eac i e oxygen species (ROS), which is o en associa ed
wi h ac i e ATP syn hesis (Rosko e al., 2019).
OLs ob ain glucose om he bloods eam h ough he up ake o he
glucose anspo e GLUT1, which is exp essed bo h in he endo helial
FIGURE2
Roles o oligodend ocy es in heal h and disease. The le sec ion depic s physiological unc ions, including blood–b ain ba ie suppo , ion
homeos asis, myelina ion and me abolic suppo h ough glucose and lac a e anspo , as well as a y acid p o ision du ing hypoglycaemia. The igh
sec ion illus a es pa hological p ocesses: (1) Age- ela ed changes, ep esen ed by hinning myelin, dis up ed axon-oligodend ocy e suppo , and
ma ke s o DNA and mi ochond ial dys unc ion due o aging. (2) Me abolic b eakdown, highligh ing dis up ed glucose and lac a e anspo ,
mi ochond ial dys unc ion, and neu oin lamma ion om ac i a ed mic oglia and cy okines. (3) P o ein agg ega ion in neu odegene a i e diseases,
showing he p og ession om heal hy oligodend ocy es o dys unc ion and neu onal degene a ion, linked o amyloid plaques (AD), α-synuclein (MSA),
and p o ein inclusions (ALS). Illus a ion c ea ed wi h BioRende .com.
López-Mugu uza e al. 10.3389/ nana.2025.1557214
F on ie s in Neu oana omy 05 on ie sin.o g
cells o he BBB and on he ou e memb ane o he OLs hemsel es
(Philips and Ro hs ein, 2017; Simpson e al., 2007). Once glucose en e s
he cell, i can beu ilized in a ious biochemical pa hways o s o ed as
glycogen, as seen in as ocy es (Lee e al., 2021), hough i is unclea
whe he oligodend ocy es s o e glycogen. The glycoly ic pa hway
gene a es py u a e as i s end-p oduc . Py u a e can ei he be anspo ed
in o he mi ochond ia and con e ed o ace yl-CoA o en y in o he
ci ic acid cycle o be educed o lac a e by lac a e dehyd ogenase (Philips
and Ro hs ein, 2017; Zanga i e al., 2020). One way in which OLs p o ide
me abolic suppo o axons is by exchanging glucose me abolic
de i a i es h ough a ious monoca boxyla e anspo e s (MCTs) once
hey ha e been me abolized (Na e e al., 2023).
OLs exp ess MCT1in hei myelin, which selec i ely anspo s
lac a e o neu ons, whe e i is aken up ia MCT2 (Lee e al., 2012), a
p ocess e e ed o as he oligodend ocy e-neu on lac a e shu le
(Tepa če ić, 2021). Dis up ion o his shu le, such as h ough
condi ional dele ion o MCT1in OLs, esul s in signi ican axonal
inju y and mo o neu on dea h in animal models (Philips e al., 2021).
Mo eo e , a de iciency in ei he MCT1 o MCT2 leads o axonal
degene a ion in b ain slices. In e es ingly, only he loss o MCT1 can
be escued by exogenous L-lac a e, as MCT2 acili a es he di ec
anspo o lac a e in o axons (Peppe e al., 2018).
Simila ly, ke one bodies, which ac as an al e na i e ene gy sou ce
o a ious cell ypes, a e expo ed by endo helial cells and aken up by
OLs and as ocy es ia MCT1, and by neu ons h ough MCT2, owing
o hei monoca boxyla e s uc u e (Jensen e al., 2020; Lee e al., 2012).
Among hem a e ace oace ic acid and β-hyd oxybu y a e, which a e
p ima ily p oduced om a y acids in he li e , hough as ocy es also
con ibu e o hei syn hesis (Fe nandes e al., 2025). Once inside he
cell, ke one bodies can be con e ed in o ace yl-CoA, simila o
py u a e, and en e he TCA cycle o uel OXPHOS o high ATP yield
(55,56). Al e na i ely, ke one bodies may beused o lipid syn hesis
and myelin p oduc ion. Speci ically, OPCs and OLs can u ilize ke one
bodies o myelin lipid syn hesis, wi h a po en ial ole in ATP
gene a ion, pa icula ly du ing ac i e de elopmen al myelina ion
(Kope e al., 1981; Poduslo and Mille , 1991; Tepa če ić, 2021).
3.2 Insigh s in o lipid me abolism
To unde s and u he he ole o lipid me abolism in OLs beyond
myelin ecycling, i is impo an o del e deepe in o how a y acid
β-oxida ion and au ophagy coo dina e ene gy managemen and myelin
in eg i y. Au ophagy, pa icula ly he au ophagy-lysosomal pa hway,
no only acili a es he ecycling o lipids om myelin deg ada ion bu
also helps o egula e he in e nal lipid s o es o OLs. Due o he high
lipid demand equi ed o myelina ion, his s ep is belie ed o bec ucial
in OL unc ion (Abe e al., 2022; Belg ad e al., 2020).
Fa y acids unde go β-oxida ion, a se ies o enzyma ic deg ada ions
in he mi ochond ia ha p oduce ace yl-CoA o suppo OXHPOS,
p o iding ene gy o me abolically demanding unc ions (Hou en and
Wande s, 2010). Eme ging esea ch indica es ha a y acids can ac as
an al e na i e ene gy sou ce when glucose is sca ce. Bo h OLs and
as ocy es may u ilize a y acids o gene a e ene gy o ans e
me aboli es o axons, he eby suppo ing neu onal unc ion (Lee e al.,
2021; Mi e al., 2023; Na e e al., 2023). In D osophila, esea ch shows
ha when glycolysis is comp omised, glial cells depend on mi ochond ial
a y acid b eakdown and ke one body p oduc ion o sus ain neu onal
unc ion. This s udy unde sco es ha du ing ex ended pe iods o
s a a ion o glucose dep i a ion, glial a y acid me abolism is i al o
main aining neu onal ene gy and ly su i al. Addi ionally, glial cells
se e as me abolic senso s, mobilizing lipid ese es o main ain b ain
ene gy balance (McMullen e al., 2023; Schulz e al., 2015).
In an ex i o s udy o op ic ne es, OLs showed no able esilience o
glucose dep i a ion. Indeed, du ing low glucose condi ions, axonal ATP
and ac ion po en ials depend on a y acid β-oxida ion. OLs appea o
p o ide an ene gy ese e o whi e ma e and p o ec axons om
conduc ion blocks, al hough hey do no suppo high equency spiking.
Dis up ion o GLUT1in OLs esul s in myelin imbalance and g adual
demyelina ion, sugges ing ha impai ed myelin egula ion may con ibu e
o myelin hinning in aging and disease. These indings highligh he
c i ical ole o oligodend oglial lipid me abolism in main aining b ain
unc ion du ing ene gy sho ages (Asadollahi e al., 2024).
Fu he mo e, pe oxisomes, small o ganelles in euka yo ic cells
in ol ed in me abolism and de oxi ica ion o ROS, con ibu e o lipid
me abolism by p ocessing e y long chain a y acids, simila o
mi ochond ia (Kassmann e al., 2007). These o ganelles a e abundan
in he CNS, pa icula ly in glial cells, and a e ound in he inne
egions o he myelin shea h (Kuma e al., 2024; Riche e al., 2014).
Dis up ion o pe oxisomal p o eins, known as pe oxins, can lead o
whi e ma e abno mali ies, sugges ing a key ole o pe oxisomes in
axonal suppo and myelin main enance (Kassmann, 2014).
4 Dys unc ion a he axon-myelin uni
and neu odegene a ion
The ex ao dina y ene gy demands o he b ain ende i pa icula ly
ulne able o bioene ge ic dis up ions (Figu e2). Long, myelina ed axons
a e especially a ec ed by de ec i e ene gy me abolism due o hei high
ene gy equi emen s associa ed wi h ansmission and o he essen ial
main enance p ocesses. Gi en ha OLs play a c ucial ole in he ophic
suppo o myelina ed axons, bioene ge ic dys unc ion in hese cells has
become he ocus o nume ous ecen s udies on neu odegene a ion. In
MS, in lamma ion causes a selec i e loss o OLs ha ul ima ely leads o
demyelina ion, axonal damage, and neu odegene a ion. Consequen ly,
oligodend oglial dys unc ion has assumed a cen al ole in he s udy o
his disease (T app and Na e, 2008). Me abolomic s udies ha e e ealed
ha pa ien s wi h MS exhibi nume ous al e a ions in ma ke s ela ed o
glucose, lac a e, and a y acid me abolism in ce eb ospinal luid (López-
Mugu uza and Ma u e, 2023). Addi ionally, in p og essi e MS lesions, a
s a e o i ual hypoxia occu s due o de ec s in mic oci cula ion and he
elease o oxins ha in e e e wi h ene gy me abolism (Lassmann, 2003),
which is consis en wi h oligodend oglial me abolic dys unc ion. Unde
hese me abolic s ess condi ions ypical o MS lesions, s udies in human
OLs ha e shown ha hese p edominan ly glycoly ic cells educe hei
me abolic a e, p io i izing hei own su i al a he expense o ophic
suppo o he axon (Rone e al., 2016). This phenomenon may cons i u e
a mechanism o axonal damage p eceding he e ac ion o myelin, a
hallma k o MS (Me z e al., 2007). Fu he mo e, human OPCs, also
p edominan ly glycoly ic bu me abolically mo e ac i e, did no educe
hei me abolism unde me abolic s ess condi ions, which becomes oxic
o hese cells and hinde s emyelina ion (Rone e al., 2016). On he o he
hand, he high ene gy demands o he syn hesis and main enance o
myelin compel OLs o u ilize mi ochond ial OXPHOS o ATP
p oduc ion as a complemen o glycolysis (Ha is and A well, 2012).
López-Mugu uza e al. 10.3389/ nana.2025.1557214
F on ie s in Neu oana omy 06 on ie sin.o g
Addi ionally, de ec s in mi ochond ia con ibu e o axonal damage and
neu odegene a ion in MS. Some cha ac e is ic mi ochond ial al e a ions
obse ed in whi e ma e lesions include de ec s in he machine y
esponsible o OXPHOS and m DNA, leading o oxida i e s ess, among
o he s (Wi e e al., 2019). Fu he mo e, in an animal model o MS, such
as expe imen al au oimmune encephalomyeli is (EAE), al e a ions such
as mi ochond ial depola iza ion and educed exp ession o complex Io
he espi a o y chain p ecede demyelina ion and axonal degene a ion
(Sadeghian e al., 2016). Howe e , e idence ega ding whe he
mi ochond ial dys unc ion in MS occu s wi hin OLs hemsel es o in
o he componen s o whi e ma e , such as as ocy es and axons, emains
limi ed. The inding ha human he edi a y mi ochond ial diseases, such
as Lebe ’s he edi a y op ic neu opa hy (LHON), cause oligodend oglial
cell dea h and demyelina ion (78) and inc ease he isk o de eloping MS
(Vanopdenbosch e al., 2000) suppo s his no ion. Fo ins ance, Mahad
e al. (2008) iden i ied de ec s in complex IV o he espi a o y chain in
OLs wi hin ischemic ac i e lesions (Mahad e al., 2008). Mo e ecen ly, a
s udy conduc ed in animals wi h EAE iden i ied oxida i e s ess and
al e a ions in mi ochond ial mo phology in oligodend ocy es p io o he
in il a ion o in lamma o y cells (S eudle e al., 2022). Addi ionally,
double-s and b eaks in m DNA in mice induce mi ochond ial
dys unc ion and apop osis in OLs, leading o subsequen demyelina ion
(Madsen e al., 2017).
On he o he hand, neu odegene a i e diseases associa ed wi h
aging sha e a key elemen : he p og essi e loss o neu ons as a cen al
igge o hei pa hogenesis. Fu he mo e, bioene ge ic dys unc ion
and glucose hypome abolism a e cha ac e is ics common o
Alzheime ’s disease (AD), Pa kinson’s disease (PD), amyo ophic
la e al scle osis (ALS), and Hun ing on’s disease (HD), among o he s
(Yang e al., 2023). Howe e , wi h aging, whi e ma e is a ec ed as
much as g ay ma e (Gunning-Dixon e al., 2009), and dys unc ion o
he axon-myelin coupling has eme ged as a po en ial neu opa hological
mechanism in nume ous neu odegene a i e diseases. In AD, he
leading cause o demen ia and he mos p e alen neu odegene a i e
diso de , signi ican damage is obse ed in he whi e ma e o
pos mo em b ains (Gouw e al., 2008; Nas abady e al., 2018), e en in
he p eclinical s ages o he disease (Dean e al., 2017; Hoy e al., 2017),
along wi h nume ous pa hological changes in he exp ession o
oligodend oglial genes ela ed o myelina ion (Ma hys e al., 2019).
This and o he e idence suppo he no ion ha OLs no only espond
o pa hology bu may also con ibu e causally o AD (Ba zokis, 2011;
Han e al., 2022). AD is cha ac e ized a he molecula le el by
ex acellula deposi s o β-amyloid (Aβ) and in acellula accumula ion
o phospho yla ed au; howe e , he exac ole o hese agg ega es in
he onse o he disease has ye o each a consensus wi hin he scien i ic
communi y. One o he mos s udied hypo heses is he amyloid cascade
hypo hesis, which posi s ha he accumula ion o soluble oligome s o
Aβ igge s he disease (Selkoe, 2008). In e es ingly, amyloidosis is
signi ican ly inc eased in animal models o amilial AD ha also ca y
oligodend ocy e-speci ic mu a ions ha impai o myelin in eg i y
(Depp e al., 2023). These indings sugges a causal ela ionship
be ween oligodend oglial dys unc ion and Aβ deposi s (Na e e al.,
2023) and ha dis up ion o oligodend ocy e-axon coupling se e ely
comp omises ophic suppo o axons in AD, p omo ing Aβ
accumula ion due o de ec s in axonal anspo and lysosomal
deg ada ion. In u n, he accumula ion o Aβ, which is also p esen in
whi e ma e (Iwamo o e al., 1997), could nega i ely impac myelin-
axon coupling, he eby c ea ing a icious cycle (Mo e al., 2018).
Ano he neu odegene a i e disease o which oligodend oglial
me abolic dys unc ion appea s o con ibu e is ALS, cha ac e ized by he
p og essi e loss o mo o neu ons in he ce eb al co ex and spinal co d,
leading o muscle a ophy and espi a o y pa alysis 3–5 yea s a e he
onse o ini ial symp oms. Howe e , ALS is now conside ed a “non-cell
au onomous” disease in which glial cells may con ibu e o disease
p og ession by inducing o exace ba ing damage o mo o neu ons
(Philips and Ro hs ein, 2014). In ac , al e a ions in whi e ma e occu in
bo h animal models and ALS pa ien s, leading o he hypo hesis ha
oligodend oglial dys unc ion is a ele an ac o in he pa hogenesis o he
disease (Ra aele e al., 2021). Indeed, oligodend oglial inclusions o
mu a ed p o eins associa ed wi h ALS like TDP-43, FUS and SOD1 ha e
been ound in nume ous cases o bo h spo adic and amilial ALS (Mo
e al., 2018). Al hough hese abe an p o eins a e exp essed ubiqui ously,
hey pa icula ly a ec mo o neu ons, po en ially due o he high ene gy
demands o hese cells. Thus, hese inclusions could physically dis up he
anspo and di usion o me aboli es such as lac a e om OLs o axons
by obs uc ing myelinic channels (Mo e al., 2018). Mo e speci ically, loss
o OLs appea s in he spinal co d o SOD1-G93A mice, an animal model
o ALS, p io o he onse o symp oms indica i e o mo o neu on
degene a ion (Kang e al., 2013; Philips e al., 2013). These OLs a e
eplaced by new OPCs ha , howe e , exhibi educed exp ession o key
ma u a ion p o eins such as myelin basic p o ein (MBP) and
monoca boxyla e anspo e 1 (MCT1), esul ing in demyelina ion
(Philips e al., 2013). Fu he mo e, since MCT1 is a key anspo e o
oligodend ocy e-axon me abolic coupling (Lee e al., 2012), OLs
exp essing SOD1-G93A would ha e hei capaci y o p o ide ophic
suppo o associa ed axons limi ed, he eby accele a ing disease
p og ession (Mo e al., 2018).
On he o he hand, he p ima y his opa hological hallma k o
mul iple sys em a ophy (MSA)—a a e and agg essi e neu odegene a i e
diso de —is he p esence o cy oplasmic inclusions o α-synuclein
(α-Syn) agg ega es p edominan ly wi hin oligodend ocy es, o ming glial
cy oplasmic inclusions (GCIs). MSA sha es many ea u es wi h o he
synucleinopa hies, such as Pa kinson’s disease. Mos cases o MSA a e
spo adic, al hough a mu a ion in he COQ2 gene, which encodes he
enzyme esponsible o coenzyme Q10 syn hesis, has been linked o he
disease in a Japanese pa ien coho (Poewe e al., 2022). Al hough α-Syn
accumula ion does no lead o signi ican oligodend oglial cell dea h, i
induces demyelina ion, i on o e load, and dis up ion o au ophagy,
e en ually igge ing se e e neu onal loss (Poewe e al., 2022). I emains
unclea whe he OLs hemsel es pa hologically up egula e α-Syn
exp ession wi hin he b ain o i hey up ake α-Syn sec e ed by neu ons
in MSA. Fu he mo e, as oglial and neu onal inclusions, as well as
axonal dys unc ion and neu onal degene a ion, a e also obse ed;
howe e , p eclinical and pos mo em s udies indica e ha MSA is
p ima ily an oligodend ogliopa hy (Han e al., 2022). Among he
candida es esponsible o oligodend oglial dys unc ion is ubulin
polyme iza ion-p omo ing p o ein (TPPP/p25α), which is speci ic o OLs
and p esen in GCIs (Ko ács e al., 2004). Unde no mal condi ions, his
p o ein colocalizes wi h myelin basic p o ein (MBP), bu in MSA b ains,
i eloca es o he cell body (Song e al., 2007) and con ibu es o he
o ma ion o an oligodend ocy e-speci ic α-Syn s ain wi h high
neu odegene a i e po en ial (Fe ei a e al., 2021). In e es ingly, TPPP/
p25α has been epo ed o colocalize wi h mi ochond ial p o eins in he
cy oplasm o OLs in bo h spo adic MSA pa ien s and a amilial MSA
pa ien ca ying he COQ2 gene mu a ion (O a e al., 2014). Addi ionally,
i was p e iously obse ed ha α-Syn exp ession speci ically in OLs,
López-Mugu uza e al. 10.3389/ nana.2025.1557214
F on ie s in Neu oana omy 07 on ie sin.o g
a he han in neu ons, leads o a dec ease in b ain le els o glial-de i ed
neu o ophic ac o (GDNF) (Ubhi e al., 2010). Gi en ha neu ons
unde go degene a ion in MSA, hese indings sugges ha mi ochond ial
dys unc ion may induce he eloca ion o TPPP/p25α wi hin OLs and a
pa hological inc ease in α-Syn exp ession, esul ing in impai ed ophic
suppo om OLs o neu ons (Mo e al., 2018).
In summa y, subs an ial e idence sugges s ha me abolic dys unc ion
in OLs signi ican ly con ibu es o he pa hogenesis o a ious
neu odegene a i e diseases, including MS, AD, ALS and MSA. The
age- ela ed de e io a ion o myelin can dis up me abolic coupling
be ween OLs and axons, dep i ing neu ons o i al ophic suppo and
esul ing in axonal damage and neu odegene a ion. Consequen ly,
enhancing myelin-axon me abolic coupling ep esen s a p omising
he apeu ic a ge o u u e esea ch in neu odegene a ion.
5 The apeu ic implica ions and u u e
di ec ions
As ou unde s anding o OL myelin p oduc ion and me abolic
egula ion deepens, new s a egies a e eme ging o enhance
neu op o ec ion and add ess he me abolic dys unc ions linked o
neu odegene a i e diseases (Figu e2). Recen ad ances emphasize he
po en ial o a ge ed in e en ions aimed a co ec ing hese dys unc ions
(Cunnane e al., 2020; Han e al., 2022). Neu odegene a i e diso de s a e
challenging o ea due o hei p og essi e and mul i ac o ial na u e.
Howe e , hese diseases sha e common ea u es, including sys emic
neu on loss in he mo o , senso y, and cogni i e sys ems, leading o a
spec um o symp oms and me abolic changes in b ain ene gy egula ion
(P ocaccini e al., 2016). Cu en ly, no disease-modi ying he apies can
e e se o hal disease p og ession. Exis ing ea men s p ima ily manage
symp oms, highligh ing he u gen need o he apies ha a ge he
unde lying neu opa hogenesis (Cleland e al., 2021).
Remyelina ion he apies o MS aim o p omo e he epai o
o ma ion o new myelin by using a ious d ugs and app oaches
(Kan a ci, 2019; Lassmann, 2018). Se e al compounds, such as
benz opine, clemas ine, and que iapine, ha e been shown o enhance
OL ec ui men , su i al, and di e en ia ion by a ge ing ecep o s
like musca inic ace ylcholine (M1) and his amine (H1, H3) (Jiang
e al., 2011; K eme e al., 2019; Münzel and Williams, 2013).
Opicinumab, a monoclonal an ibody agains LINGO-1, also shows
p omise by p omo ing emyelina ion, hough clinical ial esul s ha e
been mixed (Lassmann, 2018; Le in and Kaplan, 2017). While
emyelina ion is e ec i e in ea ly MS s ages, cell deple ion and
in lamma ion in ad anced s ages limi i s success (He e al., 2021).
Recen esea ch highligh s he po en ial o a ge ing
monoca boxyla e anspo e s (MCTs) o enhance neu op o ec ion in
diseases like AD, MS, and ALS, whe e axonal in eg i y is comp omised
(Jha and Mo ison, 2018; López-Mugu uza and Ma u e, 2023).
Inhibi ion o MCT1 in OLs leads o axonal damage, bu lac a e
supplemen a ion can e e se his. Fu he mo e, boos ing MCT1in
OLs and MCT2 in neu ons has been shown o p e en axonal
degene a ion, imp o e ene gy me abolism, and educe oxida i e
s ess, demons a ing po en ial in neu odegene a ion models
(Villoslada, 2016; Wu e al., 2023).
Ke ogenic die s, which a e high in a and low in ca bohyd a es,
ele a e ke one body p oduc ion, p o iding an al e na i e ene gy
sou ce o he b ain (Tao e al., 2022). In neu odegene a i e diseases
like MS, ke ogenic die s ha e shown p omise in educing oxida i e
s ess and in lamma ion, bo h o which con ibu e o OL dys unc ion
(S o oni and Plan , 2015). S udies sugges ha ke ogenic die s educe
neu oin lamma ion and p omo e he con e sion o M1 mic oglia o a
p o ec i e M2 pheno ype in expe imen al MS models, leading o
imp o ed mo o unc ion and dec eased demyelina ion (Sun e al.,
2023). Mo eo e , ke ogenic die s enhance mi ochond ial unc ion,
which is c ucial o main aining ene gy homeos asis in he b ain and
suppo ing OLs in hei myelin p oduc ion (Yang e al., 2019).
Lipids, pa icula ly a y acids, a e ecognized o hei complex
oles in neu odegene a i e diseases. Sho -chain a y acids (SCFAs),
p oduced by gu mic obio a om die a y ibe (Kouspa ou e al.,
2023), ha e been linked o a educ ion in amyloid-be a accumula ion,
a hallma k o AD (Wysoczański e al., 2016). Sodium bu y a e, a well-
s udied SCFA, has shown p omise in imp o ing cogni i e and
memo y pe o mance in AD models (Dyall, 2015). Medium-chain
a y acids (MCFAs), ound in dai y and coconu oil (A allone e al.,
2019), ac as agonis s o pe oxisome p oli e a o -ac i a ed ecep o s
(PPARs), which in luence b ain unc ion by enhancing insulin
sensi i i y and modula ing in lamma ion, pa icula ly in diseases like
PD and MS (Chang e al., 2015).
Long-chain a y acids (LCFAs) a e essen ial o b ain unc ion,
bu hei e ec s a y depending on he ype and concen a ion.
Polyunsa u a ed a y acids (PUFAs), such as omega-3 (e.g., DHA and
EPA) and omega-6 a y acids, show neu op o ec i e p ope ies in
managing neu odegene a i e diseases (Kouspa ou e al., 2023;
Wysoczański e al., 2016). These PUFAs help egula e in lamma ion,
p o ec agains oxida i e s ess, and s abilize neu onal memb anes
(Dyall, 2015). Fo example, DHA has been shown o educe
neu oin lamma ion and p ese e synap ic in eg i y, which is c ucial
in AD and PD (A allone e al., 2019; Chang e al., 2015). Thei e ec s
s em om hei abili y o modula e immune esponses and p omo e
memb ane luidi y, aiding neu onal esilience du ing
neu odegene a ion (Giacobbe e al., 2020; Yang e al., 2011).
Con e sely, sa u a ed LCFAs like palmi ic acid (PA) a e linked o
neu o oxici y h ough he ac i a ion o in lamma o y pa hways,
inc easing neu oin lamma ion— a hallma k o neu odegene a i e
diseases (Vesga-jiménez e al., 2022). PA ac i a es oll-like ecep o s
(TLRs) and he NF-κB pa hway, which leads o oxida i e s ess and
cellula dys unc ion (Oso io e al., 2020). In con as , monounsa u a ed
a y acids like oleic acid (OA) ha e neu op o ec i e e ec s (U so and
Zhou, 2021). OA s abilizes cell memb anes, suppo s axonal g ow h,
and coun e ac s PA-induced in lamma ion. I also helps main ain
mi ochond ial heal h and lipid homeos asis, suppo ing neu al epai
and educing neu odegene a i e damage (Beaulieu e al., 2021;
Eynaudi e al., 2021; U so and Zhou, 2021).
6 Conclusion
The use o omics echnology du ing he las decade has
subs an ia ed he pionee ing ideas o del Río-Ho ega abou he
unc ional ole o oligodend ocy e he e ogenei y in axon-myelin uni
and beyond. In pa icula , we now know how newly o med
oligodend ocy es handle calcium homeos asis du ing ma u a ion; ha
pe i ascula oligodend oglia con ibu es o BBB o ma ion; and ha
oligodend ocy es and hei p ogeni o s a e immunocompe en du ing
in lamma ion (Figu e2). This opens he ga e o he de elopmen o
López-Mugu uza e al. 10.3389/ nana.2025.1557214
F on ie s in Neu oana omy 08 on ie sin.o g
he apeu ic in e en ions a ge ing di ec ly oligodend ocy es and
myelin o amelio a e neu odegene a i e and demyelina ing diseases.
In u n, ecen esea ch g ounded Río-Ho ega’s ideas abou
oligodend oglia as a p o ide o ophic/me abolic suppo o axons
exchanging glucose me abolic de i a i es h ough monoca boxyla e
anspo e s. S ikingly, indi ec e idence shows ha oligodend oglia
may p o ide myelin-de i ed a y acids o suppo axonal unc ion
du ing hypoglycaemia (Asadollahi e al., 2024).
On he o he hand, oligodend ocy e dys unc ion may con ibu e
o AD pa hology onse and p og ession as amyloidosis occu s in
oligodend ocy e-speci ic mu a ions ha impai myelin in eg i y.
Likewise, oligodend oglial inclusions o mu a ed p o eins associa ed
wi h ALS may dis up he anspo and di usion o me aboli es o
axons p io o he onse o symp oms. Mo eo e , MSA oligodend opa hy
includes he o ma ion o an oligodend ocy e-speci ic α-Syn s ain wi h
high neu odegene a i e po en ial. Finally, myelin aging can dis up
me abolic coupling be ween OLs and axons esul ing in axonal
neu odegene a ion. Consequen ly, enhancing myelin-axon me abolic
coupling ep esen s a p omising he apeu ic a ge o u u e esea ch
in neu odegene a ion. This includes boos ing MCT1 o suppo ene gy
me abolism, ke ogenic and a y acid die s o educe neu oin lamma ion
and demyelina ion as well as enhancing mi ochond ial unc ion o help
OLs main ain myelin p oduc ion and p ese e axonal in eg i y.
Au ho con ibu ions
EL-M: W i ing– o iginal d a , W i ing– e iew & edi ing. CP-M:
W i ing– o iginal d a , W i ing– e iew & edi ing. FP-C: W i ing–
o iginal d a , W i ing– e iew & edi ing. CM: W i ing– o iginal
d a , W i ing – e iew & edi ing. AR: W i ing – o iginal d a ,
W i ing– e iew & edi ing.
Funding
The au ho (s) decla e ha inancial suppo was ecei ed o he
esea ch and/o publica ion o his a icle. This wo k was unded by
he Minis e o Science and Resea ch (g an no. PID2022-
143020OB-I00), CIBERNED (CB06/05/00), Basque Go e nmen
(g an no. IT1551-22), and EITB-Ma a oia (BIO22/ALZ/015 and
BIO23/EM/02). E.L.-M. and C.P.-M. hold ellowships om he Basque
Go e nmen and he Spanish MICINN.
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au ho s and do no necessa ily ep esen hose o hei a ilia ed
o ganiza ions, o hose o he publishe , he edi o s and he
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claim ha may bemade by i s manu ac u e , is no gua an eed o
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