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Hypomyelinating leukodystrophy-associated missense mutation in HSPD1 blunts mitochondrial dynamics

Significance Statement

Arf6 as the potential therapeutic target of neuropathies. The pictures showing the in vitro myelination illustrate that Arf6 knockdown inhibits it, suggesting that Arf6 plays a key role in forming myelinated nerves. Molecules involved in myelination processes, protecting neurons physically and physiologically, have been now focused as targets not only of demyelinating diseases but also of more broad neuropathies.

Author information

Name: Junji Yamauchi
Affiliation: Group Leader, Molecular Pharmacology Group, Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan.
Research interest: Exploring new molecules underlying myelination and demyelination in the PNS and CNS.

Hypomyelinating leukodystrophy-associated missense mutation in HSPD1 blunts mitochondrial dynamics.Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Journal Reference

Biochem Biophys Res Commun. 2015 Jul 3;462(3):275-81.

Miyamoto Y1, Eguchi T2, Kawahara K1, Hasegawa N3, Nakamura K1, Funakoshi-Tago M4, Tanoue A1, Tamura H4, Yamauchi J5.

Show Affiliations

1Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.

2The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan.

3Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan; Faculty of Pharmacy, Keio University, Minato, Tokyo 105-8512, Japan.

4Faculty of Pharmacy, Keio University, Minato, Tokyo 105-8512, Japan.

5Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan; Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan. Electronic address: [email protected]

Abstract

Myelin-forming glial cells undergo dynamic morphological changes in order to produce mature myelin sheaths with multiple layers. In the central nervous system (CNS), oligodendrocytes differentiate to insulate neuronal axons with myelin sheaths. Myelin sheaths play a key role in homeostasis of the nervous system, but their related disorders lead not only to dismyelination and repeated demyelination but also to severe neuropathies. Hereditary hypomyelinating leukodystrophies (HLDs) are a group of such diseases affecting oligodendrocytes and are often caused by missensemutations of the respective responsible genes. Despite increasing identification of gene mutations through advanced nucleotide sequencing technology, studies on the relationships between gene mutations and their effects on cellular and subcellular aberrance have not followed at the same rapid pace. In this study, we report that an HLD4-associated (Asp-29-to-Gly) mutant of mitochondrial heat shock 60-kDa protein 1 (HSPD1) causes short-length morphologies and increases the numbers of mitochondria due to their aberrant fission and fusion cycles. In experiments using a fluorescent dye probe, this mutation decreases the mitochondrial membrane potential. Also , mitochondria accumulate in perinuclear regions. HLD4-associated  HSPD1 mutant blunts mitochondrial dynamics, probably resulting in oligodendrocyte malfunction. This study constitutes a first finding concerning the relationship between disease-associated HSPD1 mutation and mitochondrial dynamics, which may be similar to the relationship between another disease-associated  HSPD1 mutation (MitCHAP-60 disease) and aberrant mitochondrial dynamics.

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