PMID- 35225888
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220304
IS  - 2035-8385 (Print)
IS  - 2035-8377 (Electronic)
IS  - 2035-8385 (Linking)
VI  - 14
IP  - 1
DP  - 2022 Feb 16
TI  - Hypomyelinating Leukodystrophy 8 (HLD8)-Associated Mutation of POLR3B Leads to 
      Defective Oligodendroglial Morphological Differentiation Whose Effect Is Reversed 
      by Ibuprofen.
PG  - 212-244
LID - 10.3390/neurolint14010018 [doi]
AB  - POLR3B and POLR3A are the major subunits of RNA polymerase III, which synthesizes 
      non-coding RNAs such as tRNAs and rRNAs. Nucleotide mutations of the RNA 
      polymerase 3 subunit b (polr3b) gene are responsible for hypomyelinating 
      leukodystrophy 8 (HLD8), which is an autosomal recessive oligodendroglial cell 
      disease. Despite the important association between POLR3B mutation and HLD8, it 
      remains unclear how mutated POLR3B proteins cause oligodendroglial cell 
      abnormalities. Herein, we show that a severe HLD8-associated nonsense mutation 
      (Arg550-to-Ter (R550X)) primarily localizes POLR3B proteins as protein aggregates 
      into lysosomes in the FBD-102b cell line as an oligodendroglial precursor cell 
      model. Conversely, wild type POLR3B proteins were not localized in lysosomes. 
      Additionally, the expression of proteins with the R550X mutation in cells 
      decreased lysosome-related signaling through the mechanistic target of rapamycin 
      (mTOR). Cells harboring the mutant constructs did not exhibit oligodendroglial 
      cell differentiated phenotypes, which have widespread membranes that extend from 
      their cell body. However, cells harboring the wild type constructs exhibited 
      differentiated phenotypes. Ibuprofen, which is a non-steroidal anti-inflammatory 
      drug (NSAID), improved the defects in their differentiation phenotypes and 
      signaling through mTOR. These results indicate that the HLD8-associated POLR3B 
      proteins with the R550X mutation are localized in lysosomes, decrease mTOR 
      signaling, and inhibit oligodendroglial cell morphological differentiation, and 
      ibuprofen improves these cellular pathological effects. These findings may reveal 
      some of the molecular and cellular pathological mechanisms underlying HLD8 and 
      their amelioration.
FAU - Sawaguchi, Sui
AU  - Sawaguchi S
AD  - Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life 
      Sciences, Hachioji 192-0392, Japan.
FAU - Suzuki, Rimi
AU  - Suzuki R
AD  - Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life 
      Sciences, Hachioji 192-0392, Japan.
FAU - Oizumi, Hiroaki
AU  - Oizumi H
AD  - Tsumura Research Laboratories, Tsumura & Co., Inashiki 200-1192, Japan.
FAU - Ohbuchi, Katsuya
AU  - Ohbuchi K
AUID- ORCID: 0000-0001-6756-3260
AD  - Tsumura Research Laboratories, Tsumura & Co., Inashiki 200-1192, Japan.
FAU - Mizoguchi, Kazushige
AU  - Mizoguchi K
AD  - Tsumura Research Laboratories, Tsumura & Co., Inashiki 200-1192, Japan.
FAU - Yamamoto, Masahiro
AU  - Yamamoto M
AD  - Tsumura Research Laboratories, Tsumura & Co., Inashiki 200-1192, Japan.
FAU - Miyamoto, Yuki
AU  - Miyamoto Y
AUID- ORCID: 0000-0001-9298-5799
AD  - Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life 
      Sciences, Hachioji 192-0392, Japan.
AD  - Department of Pharmacology, National Research Institute for Child Health and 
      Development, Setagaya 157-8535, Japan.
FAU - Yamauchi, Junji
AU  - Yamauchi J
AUID- ORCID: 0000-0002-3618-998X
AD  - Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life 
      Sciences, Hachioji 192-0392, Japan.
AD  - Department of Pharmacology, National Research Institute for Child Health and 
      Development, Setagaya 157-8535, Japan.
LA  - eng
PT  - Journal Article
DEP - 20220216
PL  - Switzerland
TA  - Neurol Int
JT  - Neurology international
JID - 101551564
PMC - PMC8884015
OTO - NOTNLM
OT  - POLR3B
OT  - Pelizaeus-Merzbacher disease (PMD)
OT  - hypomyelinating leukodystrophy (HLD)
OT  - ibuprofen
OT  - lysosome
OT  - oligodendrocyte
COIS- The authors declare no conflict of interest.
EDAT- 2022/03/01 06:00
MHDA- 2022/03/01 06:01
PMCR- 2022/02/16
CRDT- 2022/02/28 12:15
PHST- 2021/11/09 00:00 [received]
PHST- 2022/02/03 00:00 [revised]
PHST- 2022/02/14 00:00 [accepted]
PHST- 2022/02/28 12:15 [entrez]
PHST- 2022/03/01 06:00 [pubmed]
PHST- 2022/03/01 06:01 [medline]
PHST- 2022/02/16 00:00 [pmc-release]
AID - neurolint14010018 [pii]
AID - neurolint-14-00018 [pii]
AID - 10.3390/neurolint14010018 [doi]
PST - epublish
SO  - Neurol Int. 2022 Feb 16;14(1):212-244. doi: 10.3390/neurolint14010018.