Loss of Fig4 in Both Schwann Cells and Motor Neurons Contributes to CMT4J Neuropathy

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2014 Sep 5

PMID 25187576

Citations 27

Authors

Ilaria Vaccari

Antonietta Carbone

Stefano Carlo Previtali

Yevgeniya A Mironova

Valeria Alberizzi

Roberta Noseda

Cristina Rivellini

Francesca Bianchi

Ubaldo Del Carro

Maurizio DAntonio

Guy M Lenk

Lawrence Wrabetz

Roman J Giger

Miriam H Meisler

Alessandra Bolino

Affiliations

Soon will be listed here.

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.

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