Molecular mechanisms of myelin clearance in demyelinating lesions
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
Age-associated decline in regeneration capacity limits the restoration of nervous system functionality after injury. In a model for demyelination, we found that old mice fail to resolve the inflammatory response initiated after myelin damage. Aged phagocytes accumulated excessive amounts of myelin debris, which triggered cholesterol crystal formation and phagolysosomal membrane rupture and stimulated inflammasomes. Myelin debris clearance required cholesterol transporters, including apolipoprotein E. Stimulation of reverse cholesterol transport was sufficient to restore the capacity of old mice to remyelinate lesioned tissue. Thus, cholesterol-rich myelin debris can overwhelm the efflux capacity of phagocytes, resulting in a phase transition of cholesterol into crystals and thereby inducing a maladaptive immune response that impedes tissue regeneration.
Publications
- (2016) Age-related myelin degradation burdens microglia clearance function during aging. Nature Neurosci. Aug;19(8):995-8
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(See online at https://doi.org/10.1038/nn.4325) - (2016) Loss of Myelin Basic Protein Function Triggers Myelin Breakdown in Models of Demyelinating Diseases. Cell Rep. Jul 12;16(2):314-22
Weil MT, Möbius W, Winkler A, Ruhwedel T, Wrzos C, Romanelli E, Bennett JL, Enz L, Goebels N, Nave KA, Kerschensteiner M, Schaeren-Wiemers N, Stadelmann C, Simons M
(See online at https://doi.org/10.1016/j.celrep.2016.06.008) - (2016) Myelinosome formation represents an early stage of oligodendrocyte damage in multiple sclerosis and its animal model. Nature Commun. Nov 16;7:13275
Romanelli E, Merkler D, Mezydlo A, Weil MT, Weber MS, Nikić I, Potz S, Meinl E, Matznick FE, Kreutzfeldt M, Ghanem A, Conzelmann KK, Metz I, Brück W, Routh M, Simons M, Bishop D, Misgeld T, Kerschensteiner M
(See online at https://doi.org/10.1038/ncomms13275) - (2017) BCAS1 expression defines a population of early myelinating oligodendrocytes in multiple sclerosis lesions. Science Transl Med. Dec 6;9(419)
Fard MK, van der Meer F, Sánchez P, Cantuti-Castelvetri L, Mandad S, Jäkel S, Fornasiero EF, Schmitt S, Ehrlich M, Starost L, Kuhlmann T, Sergiou C, Schultz V, Wrzos C, Brück W, Urlaub H, Dimou L, Stadelmann C, Simons M
(See online at https://doi.org/10.1126/scitranslmed.aam7816) - (2018) Defective cholesterol clearance limits remyelination in the aged central nervous system. Science Jan 4. pii: eaan4183
Cantuti-Castelvetri L, Fitzner D, Bosch-Queralt M, Weil MT, Su M, Sen P, Ruhwedel T, Mitkovski M, Trendelenburg G, Lütjohann D, Möbius W, Simons M
(See online at https://doi.org/10.1126/science.aan4183) - Two adhesive systems cooperatively regulate axon ensheathment and myelin growth in the CNS. Nat Commun. 2019 Oct 22;10(1):4794
Djannatian M, Timmler S, Arends M, Luckner M, Weil MT, Alexopoulos I, Snaidero N, Schmid B, Misgeld T, Möbius W, Schifferer M, Peles E, Simons M
(See online at https://doi.org/10.1038/s41467-019-12789-z)
