TY - JOUR
T1 - Novel molecular insights into the critical role of sulfatide in myelin maintenance/function
AU - Palavicini, Juan Pablo
AU - Wang, Chunyan
AU - Chen, Linyuan
AU - Ahmar, Sareen
AU - Higuera, Juan Diego
AU - Dupree, Jeffrey L.
AU - Han, Xianlin
N1 - Publisher Copyright:
© 2016 International Society for Neurochemistry
PY - 2016/10/1
Y1 - 2016/10/1
N2 - Cerebroside sulfotransferase (CST) catalyzes the production of sulfatide, a major class of myelin-specific lipids. CST knockout (CST−/−) mice in which sulfatide is completely depleted are born healthy, but display myelin abnormalities and progressive tremors starting at 4–6 weeks of age. Although these phenotypes suggest that sulfatide plays a critical role in myelin maintenance/function, the underlying mechanisms remain largely unknown. We analyzed the major CNS myelin proteins and the major lipids enriched in the myelin in a spatiotemporal manner. We found a one-third reduction of the major compact myelin proteins (myelin basic protein, myelin basic protein, and proteolipid protein, PLP) and an equivalent post-developmental loss of myelin lipids, providing the molecular basis behind the thinner myelin sheaths. Our lipidomics data demonstrated that the observed global reduction of myelin lipid content was not because of an increase of lipid degradation but rather to the reduction of their synthesis by oligodendrocytes. We also showed that sulfatide depletion leads to region-specific effects on non-compact myelin, dramatically affecting the paranode (neurofascin 155) and the major inner tongue myelin protein (myelin-associated glycoprotein). Moreover, we demonstrated that sulfatide promotes the interaction between adjacent PLP extracellular domains, evidenced by a progressive decline of high molecular weight PLP complexes in CST−/− mice, providing an explanation at a molecular level regarding the uncompacted myelin sheaths. Finally, we proposed that the dramatic losses of neurofascin 155 and PLP interactions are responsible for the progressive tremors and eventual ataxia. In summary, we unraveled novel molecular insights into the critical role of sulfatide in myelin maintenance/function. (Figure presented.) Cerebroside sulfotransferase (CST) catalyzes the production of sulfatide, a major class of myelin-specific lipids. CST knockout (CST−/−) mice in which sulfatide is completely depleted are born healthy, but display myelin abnormalities We show in our study that sulfatide depletion leads to losses of myelin proteins and lipids, and impairment of myelin functions, unraveling novel molecular insights into the critical role of sulfatide in myelin maintenance/function.
AB - Cerebroside sulfotransferase (CST) catalyzes the production of sulfatide, a major class of myelin-specific lipids. CST knockout (CST−/−) mice in which sulfatide is completely depleted are born healthy, but display myelin abnormalities and progressive tremors starting at 4–6 weeks of age. Although these phenotypes suggest that sulfatide plays a critical role in myelin maintenance/function, the underlying mechanisms remain largely unknown. We analyzed the major CNS myelin proteins and the major lipids enriched in the myelin in a spatiotemporal manner. We found a one-third reduction of the major compact myelin proteins (myelin basic protein, myelin basic protein, and proteolipid protein, PLP) and an equivalent post-developmental loss of myelin lipids, providing the molecular basis behind the thinner myelin sheaths. Our lipidomics data demonstrated that the observed global reduction of myelin lipid content was not because of an increase of lipid degradation but rather to the reduction of their synthesis by oligodendrocytes. We also showed that sulfatide depletion leads to region-specific effects on non-compact myelin, dramatically affecting the paranode (neurofascin 155) and the major inner tongue myelin protein (myelin-associated glycoprotein). Moreover, we demonstrated that sulfatide promotes the interaction between adjacent PLP extracellular domains, evidenced by a progressive decline of high molecular weight PLP complexes in CST−/− mice, providing an explanation at a molecular level regarding the uncompacted myelin sheaths. Finally, we proposed that the dramatic losses of neurofascin 155 and PLP interactions are responsible for the progressive tremors and eventual ataxia. In summary, we unraveled novel molecular insights into the critical role of sulfatide in myelin maintenance/function. (Figure presented.) Cerebroside sulfotransferase (CST) catalyzes the production of sulfatide, a major class of myelin-specific lipids. CST knockout (CST−/−) mice in which sulfatide is completely depleted are born healthy, but display myelin abnormalities We show in our study that sulfatide depletion leads to losses of myelin proteins and lipids, and impairment of myelin functions, unraveling novel molecular insights into the critical role of sulfatide in myelin maintenance/function.
KW - cerebroside sulfotransferase
KW - myelin lipidome
KW - myelin-associated glycoprotein
KW - proteolipid protein
KW - shotgun lipidomics
KW - sulfatide
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U2 - 10.1111/jnc.13738
DO - 10.1111/jnc.13738
M3 - Article
C2 - 27417284
AN - SCOPUS:84981356260
SN - 0022-3042
VL - 139
SP - 40
EP - 54
JO - Journal of neurochemistry
JF - Journal of neurochemistry
IS - 1
ER -