Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy

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 F...

Full description

Saved in:
Bibliographic Details
Published in:Human molecular genetics 2015-01, Vol.24 (2), p.383-396
Main Authors: Vaccari, Ilaria, Carbone, Antonietta, Previtali, Stefano Carlo, Mironova, Yevgeniya A, Alberizzi, Valeria, Noseda, Roberta, Rivellini, Cristina, Bianchi, Francesca, Del Carro, Ubaldo, D'Antonio, Maurizio, Lenk, Guy M, Wrabetz, Lawrence, Giger, Roman J, Meisler, Miriam H, Bolino, Alessandra
Format: Article
Language:English
Subjects:
Animals
Charcot-Marie-Tooth Disease - genetics
Charcot-Marie-Tooth Disease - metabolism
Endosomes - metabolism
Flavoproteins - genetics
Flavoproteins - metabolism
Gene Silencing
Humans
Mice
Mice, Inbred C57BL
Motor Neurons - metabolism
Myelin Sheath - metabolism
Phosphatidylinositols - metabolism
Phosphoinositide Phosphatases
Protein Transport
Schwann Cells - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddu451