2018 Theses Doctoral

Myelin is remodeled cell-autonomously by oligodendroglial macroautophagy

Aber, Etan

Myelination of axons in the CNS by oligodendrocytes (OLs) is critical for the rapid and reliable conduction of action potentials down neuronal axons, as evidenced by the severe disabilities associated with myelin loss in multiple sclerosis and other diseases of myelin. The specification, differentiation, and maturation of OLs along with myelin formation by OLs have been thoroughly characterized. How myelin is turned over, however remains unclear.
It is unsurprising that little is known about myelin turnover considering that for decades following their discovery, myelin and OLs were considered static elements in the adult nervous system. Recent evidence, however, shows that myelin in the CNS is actually plastic. Moreover, myelin remodeling in humans has been suggested to be mediated by mature OLs. As mature OLs have limited capacity to generate new myelin sheaths, we must ask whether mature OLs can remodel the myelin at preexisting myelin sheaths. One intriguing but unproven possibility is that myelin at individual internodes may be remodeled cell-autonomously by mature OLs to modulate neuronal circuit function.
Macroautophagy (MA) is responsible for the lysosome-mediated elimination of cytosolic proteins, lipids, and organelles. MA achieves this by capturing cargo in bulk or selectively in a transient, multilamellar structure known as an autophagosome (AP). In this study, we used a combination of in vivo and cellular approaches to test the hypothesis that MA in OLs may be important for myelin remodeling in the adult CNS.
We establish that myelin of individual internodes is remodeled, and does so through the coordinated efforts of endocytosis and MA. We found that autophagy protein Atg7 is essential for myelin remodeling in vivo: loss of Atg7 in OLs leads to an age-dependent increase of myelin at the internode and the formation of aberrant myelin structures, most notably myelin outfoldings. In addition, we find that MA has the potential to occur throughout the mature OL, and examination of OLs in culture suggests that formation of a mature AP structure, the amphisome, is required to facilitate the efficient degradation of myelin-containing endocytic structures. Together, we propose that myelin is a dynamic structure that is regularly remodeled through the cooperative efforts of MA and endocytosis. These findings raise the possibility that myelin remodeling is involved in neural plasticity and the tuning of neural circuits.