title: Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy.
abstract: Mutations of FIG4 are responsible for Yunis-Varón syndrome, familial epilepsy with polymicrogyria, and Charcot-Marie-Tooth type 4J neuropathy (CMT4J). Although loss of the FIG4 phospholipid phosphatase consistently causes decreased PtdIns(3,5)P₂ levels, cell-specific sensitivity to partial loss of FIG4 function may differentiate FIG4-associated disorders. CMT4J is an autosomal recessive neuropathy characterized by severe demyelination and axonal loss in human, with both motor and sensory involvement. However, it is unclear whether FIG4 has cell autonomous roles in both motor neurons and Schwann cells, and how loss of FIG4/PtdIns(3,5)P₂-mediated functions contribute to the pathogenesis of CMT4J. Here, we report that mice with conditional inactivation of Fig4 in motor neurons display neuronal and axonal degeneration. In contrast, conditional inactivation of Fig4 in Schwann cells causes demyelination and defects in autophagy-mediated degradation. Moreover, Fig4-regulated endolysosomal trafficking in Schwann cells is essential for myelin biogenesis during development and for proper regeneration/remyelination after injury. Our data suggest that impaired endolysosomal trafficking in both motor neurons and Schwann cells contributes to CMT4J neuropathy.
authors.affiliation: Division of Neuroscience, INSPE-Institute of Experimental Neurology.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Vaccari
authors.affiliation: Division of Neuroscience, INSPE-Institute of Experimental Neurology.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Carbone
authors.affiliation: Division of Neuroscience, INSPE-Institute of Experimental Neurology Department of Neurology and.
authors.forename: Stefano Carlo
authors.initials: SC
authors.lastname: Previtali
authors.affiliation: Department of Cell and Developmental Biology and.
authors.forename: Yevgeniya A
authors.initials: YA
authors.lastname: Mironova
authors.affiliation: Division of Neuroscience, INSPE-Institute of Experimental Neurology.
authors.forename: Valeria
authors.initials: V
authors.lastname: Alberizzi
authors.affiliation: Division of Neuroscience, INSPE-Institute of Experimental Neurology.
authors.forename: Roberta
authors.initials: R
authors.lastname: Noseda
authors.affiliation: Division of Neuroscience, INSPE-Institute of Experimental Neurology.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rivellini
authors.affiliation: Division of Neuroscience, INSPE-Institute of Experimental Neurology Department of Neurology and.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchi
authors.affiliation: Division of Neuroscience, INSPE-Institute of Experimental Neurology Department of Neurology and.
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Del Carro
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Antonio
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA and.
authors.forename: Guy M
authors.initials: GM
authors.lastname: Lenk
authors.affiliation: Hunter James Kelly Research Institute, State University of New York, Buffalo, NY 14203, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Wrabetz
authors.affiliation: Department of Cell and Developmental Biology and.
authors.forename: Roman J
authors.initials: RJ
authors.lastname: Giger
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA and.
authors.forename: Miriam H
authors.initials: MH
authors.lastname: Meisler
authors.affiliation: Division of Neuroscience, INSPE-Institute of Experimental Neurology bolino.alessandra@hsr.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bolino
mesh_terms: D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism; D005420:Flavoproteins / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D000072180:Phosphoinositide Phosphatases; D021381:Protein Transport; D012583:Schwann Cells / Q000378:metabolism*
chemical_list: D005420:Flavoproteins; D010716:Phosphatidylinositols; C522216:Fig4 protein, mouse; D000072180:Phosphoinositide Phosphatases