Molecular mechanisms of myelin clearance in demyelinating lesions

• Applicant: Professor Dr. Mikael Jakob Simons
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320251040

• Final Report Year: 2020

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
  Safaiyan S, Kannaiyan N, Snaidero N, Brioschi S, Biber K, Yona S, Edinger AL, Jung S, Rossner MJ, Simons M
  
• (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
  
• (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
  
• (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
  
• (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
  
• 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