Elsevier

Progress in Neurobiology

Volume 169, October 2018, Pages 24-54
Progress in Neurobiology

Review article
Oligodendrogliopathy in neurodegenerative diseases with abnormal protein aggregates: The forgotten partner

https://doi.org/10.1016/j.pneurobio.2018.07.004Get rights and content

Highlights

  • Oligodendroglial inclusions are common in neurodegenerative diseases with abnormal protein aggregates.

  • Inclusions are not mere bystanders but rather are associated with altered oligodendroglial function.

  • Altered oligodendroglial function in these diseases also occurs in the absence of oligodendroglial inclusions.

  • Oligodendrocytes play a cardinal role in the pathogenesis of neurodegenerative diseases with abnormal protein aggregates.

Abstract

Oligodendrocytes are in contact with neurons, wrap axons with a myelin sheath that protects their structural integrity, and facilitate nerve conduction. Oligodendrocytes also form a syncytium with astrocytes which interacts with neurons, promoting reciprocal survival mediated by activity and by molecules involved in energy metabolism and trophism. Therefore, oligodendrocytes are key elements in the normal functioning of the central nervous system. Oligodendrocytes are affected following different insults to the central nervous system including ischemia, traumatism, and inflammation. The term oligodendrogliopathy highlights the prominent role of altered oligodendrocytes in the pathogenesis of certain neurological diseases, not only in demyelinating diseases and most leukodystrophies, but also in aging and age-related neurodegenerative diseases with abnormal protein aggregates. Most of these diseases are characterized by the presence of abnormal protein deposits, forming characteristic and specific inclusions in neurons and astrocytes but also in oligodendrocytes, thus 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.

Section snippets

Oligodendrocytes: general aspects

In addition to neurons and astrocytes, other cells, smaller in size, are present in the nervous system. These cells, called the “third element” turned out to be two different cell types after pioneering studies by Del Rio-Hortega (1921); one of these was microglia, the other oligodendroglia. The two cell types have different origins, morphology and functions; processes in some subtypes of oligodendroglial cells run in parallel to myelin thus suggesting a relationship between oligodendroglia and

Development of oligodendroglia and myelin

Oligodendrocyte precursor cells (OPCs) proliferate in the neuroepithelium of the subventricular zone and migrate to the future white matter through extending and retracting cell processes until their definitive placements (Baumann and Pham-Dinh, 2001; Kirby et al., 2006; Miller and Mi, 2007; Hughes et al., 2013). This process is modulated by self-repulsive movements which allow a certain separation between neighboring cells (Jarjour et al., 2003; Hughes et al., 2013). Oligodendrocytes during

Diversity of OPCs/NG2-glia

OPCs are also called NG2-glia because of their expression of proteoglycan GSPG4 (NG2). These cells are not only found during the development of the nervous system; OPCs are present in the adult brain and show particular features distinct from those seen in embryonic OPCs (Káradóttir et al., 2008; Tripathi et al., 2011; Clarke et al., 2012; Vigano et al., 2013; Crawford et al., 2016). OPCs/NG2-glia is considered the fourth element in the adult central nervous system constituting about 5–10% of

Expression of neurotransmitter, hormone receptors and ion channels in oligodendrocyte lineage

A plethora of neurotransmitter and other receptors are expressed in OPCs and at different stages of oligodendroglial differentiation and maturation; these modulate, after specific ligand binding, various stages of oligodendrocyte development (Marinelli et al., 2016). GABAB receptors are expressed at early stages and their activation induces proliferation and migration of OPCs (Luyt et al., 2007). NMDA, AMPA and kainate receptors are expressed in immature and myelinating oligodendrocytes

Diversity of oligodendrocytes

Transcriptomic profiles of neurons, astrocytes and oligodendroglia have been identified using high-throughput methods (Cahoy et al., 2008; Zhang et al., 2014; Moyon et al., 2015; van Bruggen et al., 2017). Single-cell RNA sequencing revealed different subpopulations of oligodendrocytes from several brain regions of juvenile and adult mouse brain (Zeisel et al., 2015; Marques et al., 2016). A single cluster of OPCs was found in the first studies (Marques et al., 2016; Hochgerner et al., 2017).

Signals involved in OPC generation, oligodendroglia differentiation and myelination

Major knowledge of OPC generation comes from the study of the mouse spinal cord and forebrain. In the spinal cord, the first wave of generation occurs at embryonic day 12, originates from the ventral neural tube and depends upon sonic hedgehog (SHH) and Nkx6.1 and Nkx6.2 regulation of Olig 1 and Olig2 transcription (Orentas et al., 1999; Lu et al., 2000; Vallstedt et al., 2005). A second wave originates at embryonic day 15 from the dorsal spinal cord; it is not dependent on SHH but it is

Oligodendroglia and axon integrity

In addition to studies showing the role of axons in the development of oligodendroglia, several in vitro and in vivo experimental models have demonstrated that oligodendroglia are involved in support of axonal transport and axon integrity (Nave and Trapp, 2008; Lee et al., 2012; Saab et al., 2013; Beirowski, 2013; Morrison et al., 2013; White and Krämer-Albers, 2014; Simons et al., 2016). Axon outgrowth is also sustained in part by growth factors such as GDNF and BDNF produced by

Oligodendrocytes in brain aging

Human myelination is uniquely expanded and vulnerable to aging (Tse and Herrup, 2017). White matter lucencies with age were discovered by neuroimaging studies (Hachinski et al., 1987; Meyer et al., 1992). Progressive white matter decline in human brain, as revealed by magnetic resonance imaging (MRI), starts at about 45 years of age (Bartzokis et al., 2001, 2003; Sperling et al., 2014) and it is enhanced in Alzheimer’s disease (Bartzokis et al., 2003). This is accompanied by white matter

Oligodendrogliopathy

The term astrogliopathy refers to alterations of astrocytes occurring in diseases of the nervous system, includes reactive astrogliosis (mainly manifested as an increase in the amount of GFAP and in the number of astrocytes containing GFAP), and stresses the cardinal role of astrocytic dysfunction in the pathogenesis of neurological diseases (Seifert et al., 2006; Pekny and Pekna, 2014; Pekny et al., 2016; Osborn et al., 2016; Verkhratsky et al., 2017a, b). Astrocytopathy refers to decrease in

Final comments

There is extensive information about the structure and function of oligodendrocytes, oligodendroglial precursors, diversity of precursors and adult oligodendroglial cells, signaling pathways modulating maturation and development of myelinating cells, interactions of oligodendrocytes and neurons and astrocytes, and participation of oligodendrocytes in energy metabolism, as well as maintenance of axon integrity and the normal functioning of the central nervous system. Oligodendrocytes can be

Conflict of interests

No relevant data.

Acknowledgements

Part of this work was supported by the Ministry of Economy and Competitiveness, Institute of Health Carlos III (co-funded by European Regional Development Fund, ERDF, a way to build Europe) FIS PI17/00809, and co-finanzed by ERDF under the program Interreg Poctefa: RedPrion 148/16. I wish to thank Margarita Carmona, Benjamín Torrejón-Escribano and Daniela Diaz-Lucena for technical assistance, and T. Yohannan for editorial help.

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