Defective myelination in mice harboring hypomyelinating leukodystrophy-associated HSPD1 mutation

Miyamoto, Yuki; Kawahara, Kazuko; Torii, Tomohiro; Yamauchi, Junji

doi:10.1016/j.ymgmr.2017.03.003

Cited by 4 publications

(4 citation statements)

References 7 publications

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“…Additionally, HLD4-associated mutations of mitochondrion-resident heat-shock protein D1 (HSPD1) affect the fusion and fission cycle of mitochondria and their mobility in the cytoplasm. HLD4 is not likely due to the aggregation of mutated HSPD1 [23,24]. It is thus predicted that cellular pathological phenomena are simply caused by the loss-of-function of HSPD1.…”

Section: Discussionmentioning

confidence: 99%

Hypomyelinating leukodystrophy-associated mutation of RARS leads it to the lysosome, inhibiting oligodendroglial morphological differentiation

Matsumoto

Watanabe

Iibe

et al. 2019

Biochemistry and Biophysics Reports

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Pelizaeus-Merzbacher disease (PMD) is a central nervous system (CNS) demyelinating disease in human, currently known as prototypic hypomyelinating leukodystrophy 1 (HLD1). The gene responsible for HLD1 encodes proteolipid protein 1 (PLP1), which is the major myelin protein produced by oligodendrocytes. HLD9 is an autosomal recessive disorder responsible for the gene differing from the plp1 gene. The hld9 gene encodes arginyl-tRNA synthetase (RARS), which belongs to a family of cytoplasmic aminoacyl-tRNA synthetases. Herein we show that HLD9-associated missense mutation of Ser456-to-Leu (S456L) localizes RARS proteins as aggregates into the lysosome but not into the endoplasmic reticulum (ER) and the Golgi body. In contrast, wild-type proteins indeed distribute throughout the cytoplasm. Expression of S456L mutant constructs in cells decreases lysosome-related signaling through ribosomal S6 protein phosphorylation, which is known to be required for myelin formation. Cells harboring the S456L mutant constructs fail to exhibit phenotypes with myelin web-like structures following differentiation in FBD-102b cells, as part of the mammalian oligodendroglial cell model, whereas parental cells exhibit them. Collectively, HLD9-associated RARS mutant proteins are specifically localized in the lysosome with downregulation of S6 phosphorylation involved in myelin formation, inhibiting differentiation in FBD-102b cells. These results present some of the molecular and cellular pathological mechanisms for defect in myelin formation underlying HLD9.

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Section: Discussionmentioning

confidence: 99%

Hypomyelinating leukodystrophy-associated mutation of RARS leads it to the lysosome, inhibiting oligodendroglial morphological differentiation

Matsumoto

Watanabe

Iibe

et al. 2019

Biochemistry and Biophysics Reports

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“…These mutations appear to interfere with the correct conformational change required for ATP binding. Also, bioinformatics analysis predicted detrimental molecular effects for the Hsp60-p.Val98Ile and Hsp60-Gln461Glu variants, but no marked effects for the Hsp60-p.Asp29Gly, although this variant is implicated in causing disease [25,26]. In the diseases associated with Hsp60-p.Val98Ile and Hsp60-Gln461Glu variants, myelin impairment has not been confirmed or excluded, and this issue remains open for investigation.…”

Section: Mutations In the Hsp60 Genementioning

confidence: 99%

Myelin Pathology: Involvement of Molecular Chaperones and the Promise of Chaperonotherapy

et al. 2019

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The process of axon myelination involves various proteins including molecular chaperones. Myelin alteration is a common feature in neurological diseases due to structural and functional abnormalities of one or more myelin proteins. Genetic proteinopathies may occur either in the presence of a normal chaperoning system, which is unable to assist the defective myelin protein in its folding and migration, or due to mutations in chaperone genes, leading to functional defects in assisting myelin maturation/migration. The latter are a subgroup of genetic chaperonopathies causing demyelination. In this brief review, we describe some paradigmatic examples pertaining to the chaperonins Hsp60 (HSPD1, or HSP60, or Cpn60) and CCT (chaperonin-containing TCP-1). Our aim is to make scientists and physicians aware of the possibility and advantages of classifying patients depending on the presence or absence of a chaperonopathy. In turn, this subclassification will allow the development of novel therapeutic strategies (chaperonotherapy) by using molecular chaperones as agents or targets for treatment.

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“…We have succeeded in getting one line of transgenic mice harboring the isolated 1-kilobase unit of the mouse cnpase gene and cre [ 6 , 7 ] (Figs. S1 and S2).…”

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confidence: 99%

“…(A) Nco I-digested transgene's linear construct expressing Cre recombinase is composed of enhancer sequence (Refs. 6 and 7 ), mouse 46-kDa CNPase promoter [ 5 ], Cre recombinase (derived from Addgene's Cre recombinase-containing plasmid No. 62730) containing nuclear localization signal, artificial intron (derived from TaKaRa Bio's pMEI5 vector), and human chorionic gonadotropin polyadenylation signal sequence.…”

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confidence: 99%

Defective myelination in mice harboring hypomyelinating leukodystrophy-associated HSPD1 mutation

Cited by 4 publications

References 7 publications

Hypomyelinating leukodystrophy-associated mutation of RARS leads it to the lysosome, inhibiting oligodendroglial morphological differentiation

Hypomyelinating leukodystrophy-associated mutation of RARS leads it to the lysosome, inhibiting oligodendroglial morphological differentiation

Myelin Pathology: Involvement of Molecular Chaperones and the Promise of Chaperonotherapy

The promoter region of 46-kDa CNPase is sufficient for its expression in corpus callosum

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