Tau in Oligodendrocytes Takes Neurons in Sickness and in Health

Abstract

Oligodendrocytes (OLGs), the myelin-forming cells of the central nervous system (CNS), are lifelong partners of neurons. They adjust to the functional demands of neurons over the course of a lifetime to meet the functional needs of a healthy CNS. When this functional interplay breaks down, CNS degeneration follows. OLG processes are essential features for OLGs being able to connect with the neurons. As many as fifty cellular processes from a single OLG reach and wrap an equal number of axonal segments. The cellular processes extend to meet and wrap axonal segments with myelin. Further, transport regulation, which is critical for myelination, takes place within the cellular processes. Because the microtubule-associated protein tau plays a crucial role in cellular process extension and myelination, alterations of tau in OLGs have deleterious effects, resulting in neuronal malfunction and CNS degeneration. Here, we review current concepts on the lifelong role of OLGs and myelin for brain health and plasticity. We present key studies of tau in OLGs and select important studies of tau in neurons. The extensive work on tau in neurons has considerably advanced our understanding of how tau promotes either health or disease. Because OLGs are crucial to neuronal health at any age, an understanding of the functions and regulation of tau in OLGs could uncover new therapeutics for selective CNS neurodegenerative diseases.

Keywords: microtubules; multiple sclerosis; myelin; oligodendrocytes; tau.

Figure 1

The Sorting of Tau into Oligodendrocyte Processes for Neuronal Health. The key functional property of tau is its association with microtubules. The sorting of tau into OLG processes and process tips fails as a consequence of alterations in splicing mechanisms and posttranslational modifications, or when tau is fragmented. The sorting of tau into OLG processes and process tips enables correct thickness of myelin around the axon, whereas missorting of tau causes a reduction in the thickness of myelin, with deleterious effects on neuronal functions [16]. Red dots represent tau.

Figure 2

Mechanisms of Tau Regulation: Tau and the Endoplasmic Reticulum Stress Response during Progressive Degenerative Disorders of the CNS. Here we propose a model for tau-induced progressive degenerative disorders. Tau, microtubules (MTs), and the ER stress signaling are affected by each other. Tau stabilizes the MTs, whereas phosphorylated tau, MT instability, and the ER stress response progressively devastate CNS cells. The Bip chaperone frees sensor proteins (PERK, ATF, and IRE) that signal the inhibition of protein translation and promote apoptosis.