The Infantile Leukoencephalopathy-Associated Mutation of C11ORF73/HIKESHI Proteins Generates de novo Interactive Activity with Filamin A, Inhibiting Oligodendroglial Cell Morphological Differentiation.

Kohei Hattori,Kazushige Mizoguchi,Kenji Tago,Sui Sawaguchi,Yukino Kato,Yuki Miyamoto,Katsuya Ohbuchi,Arisa Ochiai,Shiori Memezawa,Takanari Sato,Junji Yamauchi,Hiroaki Ooizumi,Kazuma Tomizuka

doi:10.3390/medicines8020009

Abstract

Background: Genetic hypomyelinating diseases are a heterogeneous group of disorders involving the white matter. One infantile hypomyelinating leukoencephalopathy is associated with the homozygous variant (Cys4-to-Ser (C4S)) of the c11orf73 gene. Methods: We observed that in mouse oligodendroglial FBD-102b cells, the C4S mutant proteins but not the wild type ones of C11orf73 are microscopically localized in the lysosome. And, they downregulate lysosome-related signaling in an immunoblotting technique. Results: The C4S mutant proteins specifically interact with Filamin A, which is known to anchor transmembrane proteins to the actin cytoskeleton; the C4S mutant proteins and Filamin A are also observed in the lysosome fraction. While parental FBD-102b cells and cells harboring the wild type constructs exhibit morphological differentiation, cells harboring C4S mutant constructs do not. It may be that morphological differentiation is inhibited because expression of these C4S mutant proteins leads to defects in the actin cytoskeletal network involving Filamin A. Conclusions: The findings that leukoencephalopathy-associated C11ORF73 mutant proteins specifically interact with Filamin A, are localized in the lysosome, and inhibit morphological differentiation shed light on the molecular and cellular pathological mechanisms that underlie infantile hypomyelinating leukoencephalopathy.

Highlights

Myelin sheaths are derived from the differentiated plasma membranes of oligodendroglial cells in the central nervous system (CNS) or Schwann cells in the peripheral nervous system (PNS)
We focused on the actinbinding Filamin A [13] as the C4S mutant-specific interactive protein, since the formation and rearrangement of the actin cytoskeletal networks are essential for oligodendrocyte differentiation and myelination [22]
The present study is the first to report that the infantile leukoencephalopathy-associated C4S mutant proteins of C11ORF73 are localized in the lysosome where they aggregate and downregulate lysosome-related phosphorylating signals

Summary

Introduction

Myelin sheaths are derived from the differentiated plasma membranes of oligodendroglial cells (oligodendrocytes) in the central nervous system (CNS) or Schwann cells in the peripheral nervous system (PNS) These cells wrap multiple layers of myelin, which become the myelin sheaths, around the neuronal axons. Methods: We observed that in mouse oligodendroglial FBD-102b cells, the C4S mutant proteins but not the wild type ones of C11orf are microscopically localized in the lysosome. They downregulate lysosome-related signaling in an immunoblotting technique. Conclusions: The findings that leukoencephalopathy-associated C11ORF73 mutant proteins interact with Filamin A, are localized in the lysosome, and inhibit morphological differentiation shed light on the molecular and cellular pathological mechanisms that underlie infantile hypomyelinating leukoencephalopathy

Methods

Results

Discussion

Conclusion