Progress in Neurobiology xxx (2018) xxx-xxx Contents lists available at ScienceDirect Progress in Neurobiology journal homepage: www.elsevier.com Review article Oligodendrogliopathy in neurodegenerative diseases with abnormal protein aggregates: The forgotten partner Isidro Ferrera⁠ ,⁠ b⁠ ,⁠ c⁠ ,⁠ d⁠ ,⁠ ⁎⁠ a Department of Pathology and Experimental Therapeutics, University of Barcelona, Hospitalet de Llobregat, Spain b Service of Pathology, Bellvitge University Hospital, IDIBELL, Hospitalet de Llobregat, Spain c CIBERNED (Biomedical Network Research Centre of Neurodegenerative Diseases), Institute of Health Carlos III, Spain d Institute of Neurosciences, University of Barcelona, Spain PROOF ARTICLE INFO ABSTRACT Keywords: Oligodendrocytes are in contact with neurons, wrap axons with a myelin sheath that protects their structural Oligodendrocytes integrity, and facilitate nerve conduction. Oligodendrocytes also form a syncytium with astrocytes which in- Multiple system atrophy teracts with neurons, promoting reciprocal survival mediated by activity and by molecules involved in energy Lewy body diseases metabolism and trophism. Therefore, oligodendrocytes are key elements in the normal functioning of the cen- Tauopathy tral nervous system. Oligodendrocytes are affected following different insults to the central nervous system Alzheimer’s disease including ischemia, traumatism, and inflammation. The term oligodendrogliopathy highlights the prominent Amyotrophic lateral sclerosis Frontotemporal lobar degeneration role of altered oligodendrocytes in the pathogenesis of certain neurological diseases, not only in demyelinat- Creutzfeldt-Jakob’s disease ing diseases and most leukodystrophies, but also in aging and age-related neurodegenerative diseases with ab- Tau normal protein aggregates. Most of these diseases are characterized by the presence of abnormal protein de α-synuclein Abbreviations: 5-HT, 5-hydroxytryptamine; Aβ, β-amyloid; ABCA8, ATP binding cassette subfamily A member 8; AD, Alzheimer’s disease; ADP, adenosine diphosphate; AGD, ar- gyrophilic grain disease; ALS, amyotrophic lateral sclerosis; AMBRA-1, autophagy and beclin 1 regulator 1; AMPA, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid glutamate receptor; ANG, angiogenin; ARTAG, aging-related tau astrogliopathy; ATP, adenosine triphosphate; ATXN2, ataxin 2; BDNF, brain-derived neurotrophic factor; BIN1, bridging interac- tor 1; C9Orf72, chromosome 9 open reading frame 72; Caspr, contactin-associated proteins; CBD, corticobasal degeneration; CHMP2B, charged multivesicular body protein 2B; CJD, creutzfeldt-Jakob’s disease; CNP, 2’,3’-cyclic nucleotide-3’phosphodiesterase; CNTF, ciliary neurotrophic factor; COX, cytochrome c oxidase; Cx30, Cx32, Cx40, Cx47, connexins 30, 32, 43, 47; DARPP32, protein phosphatase 1 regulatory inhibitor subunit; DLB, dementia with Lewy bodies; Elk1, Elk1, ETS transcription factor; FACS, fluorescence-activated cell sorting; FBXO7, F-box protein 7; FGF, fibroblast growth factor; FTD, frontotemporal dementia; FTLD, frontotemporal lobar degeneration; FUS, fused-in-sarcoma; Fyn kinases, FYN proto-oncogene, Src family yrosine kinase; GABA, γ-aminobutyric acid; GalC, galactocerebroside (galactosylceramide); GDNF, glial-derived neurotrophic factor; GGT, globular glial tauopathy; Gm4, gan- glioside 4; GPR17, G-protein coupled receptor 17; GRN, granulin; GSK3, glycogen synthase kinase-3; Gsx2, GS homeobox 2; GLUT1, glial glucose transporter 1; HDAC, histone deacetylase; HSP, heat shock protein; HtrA2/OMI, HtrA serine peptidase 2; IGF-1, insulin-like growth factor 1; iPSC, induced pluripotent stem cell; KCNQ2/3, potassium voltage-gated channel subfam- ily Q member 2/3; Kv3.1, Kv1.1/1.2, potassium-gated channels; LB, Lewy body; LBD, Lewy body disease; LINGO-1, leucine-rich repeat and Ig domain containing 1; LRRK2, leucine-rich repeat kinase 2; MAG, myelin-associated glycoprotein; MAP, microtubule-associated protein; MAPK/ERK, mitogen-activated protein kinase/extracellular signal-regulated kinase; MAPT, microtubule-associated protein tau; MBP, myelin basic protein; MCT, monocarboxylate transporter; MOBP, myelin/oligodendrocyte basic protein; MOG, myelin oligodendrocyte glyco- protein; MOSP, myelin/oligodendrocyte specific protein; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MSA, multiple system atrophy; MYRF, myelin regulatory factor; Nav1.6, Nav1.1, voltage-gated sodium channels; NBR1, NBR1 autophagy cargo receptor; N-CAM, neural adhesion molecule 2; NFT, neurofibrillary tangle; NG2, proteoglycan GSPG4; Nkx.2, Nk2 homebox; Nkx.6, Nk6 homebox; NMDA, N-methyl-D-aspartate receptor; NT-3, neurotrophin 3; NUB-1, negative regulator of ubiquitin like proteins 1; Olig1, oligodendrocyte transcription factor 1; Olig2, oligodendrocyte transcription factor 2; OMgp, oligodendrocyte-myelin glycoprotein; OPC, oligodendrocyte precursor cells; OPTN, optineurin; P38, tau kinase p-38; p62, sequestosome 1; PACRG, parkin coregulated; PART, primary age-related tauopathy; PDGF, platelet-derived growth factor; PD, Parkinson’s disease; PDI, protein disulfide isomerase; PiD, Pick’s disease; PLP, proteolipid protein; PRNP, gene coding for prion protein; PrP, prion protein; PP2A, protein phosphatase 2A; PSD93/95, postsynaptic density protein 93/95; PSP, progressive supranuclear palsy; Rab5, member Ras oncogene family; SAPK/JNK, stress-activated kinase/c-Jun N-terminal kinase; SHH, sonic hedgehog; SLC, solute carrier; SOD1, super- oxide dismutase 1; Sox2, Sox8, Sox9, Sox10, SRY-box2, box8, box9, box10; SQTM1, sequestosome 1 p62; SUMO-1, small ubiquitin modifier 1; TARDBP, transactive response (TAR) DNA binding protein of 43 kD: TDP-43; TDP-43, TAR DNA binding protein; TPPP/p25, tubulin polymerization promoting protein; UBQLN, ubiquilin 2; VAL, valosin; VAMP, vesicle associated membrane protein; Wnt, Wnt family; XIAP, X-linked inhibitor of the apoptosis; Znf488, Znf536, zinc finger proteins 488 and 536. ⁎ Correspondence to: Department of Pathology and Experimental Therapeutics, University of Barcelona, Campus Bellvitge, Feixa Llarga sn, Hospitalet de Llobregat, 08907, Spain. Email address: [email protected](I. Ferrer) https://doi.org/10.1016/j.pneurobio.2018.07.004 Received 18 March 2018; Received in revised form 24 July 2018; Accepted 27 July 2018 Available online xxx 0301-0082/ © 2018. I. Ferrer Progress in Neurobiology xxx (2018) xxx-xxx TDP-43 posits, forming characteristic and specific inclusions in neurons and astrocytes but also in oligodendrocytes, thus Prion signaling their involvement in the disease. Emerging evidence suggests that such deposits in oligodendrocytes are not mere bystanders but rather are associated with functional alterations. Moreover, operative modifications in oligodendrocytes are also detected in the absence of oligodendroglial inclusions in certain diseases. The present review focuses first on general aspects of oligodendrocytes and precursors, and their development and functions, and then introduces and updates alterations and dysfunction of oligodendrocytes in selected neurodegenerative diseases with abnormal protein aggregates such as multiple system atrophy, Lewy body diseases, tauopathies, Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration with TDP-43 inclusions (TDP-43 proteinopathies), and Creutzfeldt-Jakob´s disease as a prototypical human prionopathy. tancy thus increasing the speed of the action potential with more effi- 1. Oligodendrocytes: general aspects ciency (Rosenbluth, 2009; Bakiri et al., 2011; Harris and Attwell, 2012; Babbs and Shi, 2013). The nodes of Ranvier separate internodes. Axons In addition to neurons and astrocytes, other cells, smaller in size, at the site of nodes are enriched in voltage-gated sodium channels and are present in the nervous system. These cells, called the “third ele- potassium-gated channels Nav 1.6, Nav 1.1, KCNQ2/3, Kv 3.1, Kv1.1/ ment” turned out to be two different cell types after pioneering stud- 1.2; and postsynaptic density protein 93/95 (PSD 93/95) which are all ies by Del Rio-Hortega (1921); one of these was microglia, the other crucial for saltatory nerve conduction. In addition, cytoskeletal scaffold- oligodendroglia. The two cell types have different origins, morphology ing proteins ankyrin G and B, αII/βII-spectrin and βIV-spectrin partici- and functions; processes in some subtypes of oligodendroglial cells run pate in the transport of ion channels and contribute to the assembling in parallel to myelin thus suggesting a relationship between oligoden- of axonal proteins at the node of Ranvier (Rosenbluth, 1976; Rasband et droglia and myelin (Penfield, 1924; Boullerne, 2016). Four different al., 1999; Rios et al., 2003PROOF; Devaux et al., 2003, 2004; Chen et al., 2004; types were described by Pio del Rio-Hortega as detailed in a recent re- Hartline and Colman, 2007; Duflocq et al., 2008; Susuki et al., 2013; view (Perez-Cerda et al., 2015). Type I have small round cell bodies Battefeld et al., 2014; Arancibia-Carcamo and Attwell, 2014; Barry et and large numbers of very fine cellular processes associated with thin al., 2014). Astrocytes are often located at the vicinity of the nodes of myelinated fibers in the grey matter and interfascicular white matter; Ranvier (Hildebrand, 1971a, b), but their role is not known. Type II are cuboidal with few and thick processes which trap axons lon- Oligodendrocytes can generate between 20 and 60 myelinating gitudinally in the white matter; Type III have one or two long cellular processes