Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Biomedical Genetics, 2014.
A great many molecular and metabolic components of processes of self-renewal
and cell cycle exit have been described in detail for the oligodendrocyte progenitor (O-
2A/OPC) cell—a cell needed to generate myelinating oligodendrocytes during the
development of and repair of the central nervous system—but these have not been
organized into a cohesive network with considerable predictive value. Here, we present
data indicating that activation by toxicological and physiological pro-oxidants of a
signaling pathway we recently identified and characterized, termed the Redox/Fyn/c-Cbl
(RFC) pathway, suppresses a network of mitogenic signaling molecules, including cell
cycle regulatory proteins, needed to undergo self-renewing divisions in a c-Cbldependent
manner. Unexpectedly, we find with an in vitro model of the demyelinating
lysosomal storage disorder Krabbe Disease that RFC-dependent regulation of cell
division is secondary to endolysosomal homeostasis. In this context we identify
physicochemically diverse protective agents that reduce toxicities and restore critical O-
2A/OPC progenitor cell functions, including self-renewal, by positive modulation of
lysosomal pH. Moreover, we find that toxic lipids accumulating in other lysosomal
storage disorders perturb progenitor cell behaviors by elevation of lysosomal pH,
suggesting a general principle of lyso-lipid toxicity.
