Hypomyelinating Leukodystrophy 10 (HLD10)-Associated Mutations of PYCR2 Form Large Size Mitochondria, Inhibiting Oligodendroglial Cell Morphological Differentiation
Hypomyelinating leukodystrophy 10 (HLD10) is an autosomal recessive disease related to myelin sheaths in the central nervous system (CNS). In the CNS, myelin sheaths are derived from differentiated plasma membranes of oligodendrocytes (oligodendroglial cells) and surround neuronal axons to achieve n...
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MDPI AG
2022-12-01
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| Series: | Neurology International |
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| Online Access: | https://www.mdpi.com/2035-8377/14/4/85 |
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| author | Tomohiro Torii Remina Shirai Risa Kiminami Satoshi Nishino Takanari Sato Sui Sawaguchi Nana Fukushima Yoichi Seki Yuki Miyamoto Junji Yamauchi |
| author_facet | Tomohiro Torii Remina Shirai Risa Kiminami Satoshi Nishino Takanari Sato Sui Sawaguchi Nana Fukushima Yoichi Seki Yuki Miyamoto Junji Yamauchi |
| author_sort | Tomohiro Torii |
| collection | DOAJ |
| description | Hypomyelinating leukodystrophy 10 (HLD10) is an autosomal recessive disease related to myelin sheaths in the central nervous system (CNS). In the CNS, myelin sheaths are derived from differentiated plasma membranes of oligodendrocytes (oligodendroglial cells) and surround neuronal axons to achieve neuronal functions. Nucleotide mutations of the pyrroline-5-carboxylate reductase 2 (PYCR2) gene are associated with HLD10, likely due to PYCR2’s loss-of-function. PYCR2 is a mitochondrial residential protein and catalyzes pyrroline-5-carboxylate to an amino acid proline. Here, we describe how each of the HLD10-associated missense mutations, Arg119-to-Cys [R119C] and Arg251-to-Cys [R251C], lead to forming large size mitochondria in the FBD-102b cell line, which is used as an oligodendroglial cell differentiation model. In contrast, the wild type proteins did not participate in the formation of large size mitochondria. Expression of each of the mutated R119C and R251C proteins in cells increased the fusion abilities in mitochondria and decreased their fission abilities relatively. The respective mutant proteins, but not wild type proteins also decreased the activities of mitochondria. While cells expressing the wild type proteins exhibited differentiated phenotypes with widespread membranes and increased expression levels of differentiation marker proteins following the induction of differentiation, cells harboring each of the mutant proteins did not. Taken together, these results indicate that an HLD10-associated PYCR2 mutation leads to the formation of large mitochondria with decreased activities, inhibiting oligodendroglial cell morphological differentiation. These results may reveal some of the pathological mechanisms in oligodendroglial cells underlying HLD10 at the molecular and cellular levels. |
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| spelling | doaj.art-73308e4b84da4d5db9643cbc421982192023-11-24T17:06:15ZengMDPI AGNeurology International2035-83772022-12-011441062108010.3390/neurolint14040085Hypomyelinating Leukodystrophy 10 (HLD10)-Associated Mutations of PYCR2 Form Large Size Mitochondria, Inhibiting Oligodendroglial Cell Morphological DifferentiationTomohiro Torii0Remina Shirai1Risa Kiminami2Satoshi Nishino3Takanari Sato4Sui Sawaguchi5Nana Fukushima6Yoichi Seki7Yuki Miyamoto8Junji Yamauchi9Laboratory of Ion Channel Pathophysiology, Graduate School of Brain Science, Doshisha University, Kyotanabe 610-0394, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji 192-0392, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji 192-0392, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji 192-0392, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji 192-0392, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji 192-0392, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji 192-0392, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji 192-0392, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji 192-0392, JapanLaboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji 192-0392, JapanHypomyelinating leukodystrophy 10 (HLD10) is an autosomal recessive disease related to myelin sheaths in the central nervous system (CNS). In the CNS, myelin sheaths are derived from differentiated plasma membranes of oligodendrocytes (oligodendroglial cells) and surround neuronal axons to achieve neuronal functions. Nucleotide mutations of the pyrroline-5-carboxylate reductase 2 (PYCR2) gene are associated with HLD10, likely due to PYCR2’s loss-of-function. PYCR2 is a mitochondrial residential protein and catalyzes pyrroline-5-carboxylate to an amino acid proline. Here, we describe how each of the HLD10-associated missense mutations, Arg119-to-Cys [R119C] and Arg251-to-Cys [R251C], lead to forming large size mitochondria in the FBD-102b cell line, which is used as an oligodendroglial cell differentiation model. In contrast, the wild type proteins did not participate in the formation of large size mitochondria. Expression of each of the mutated R119C and R251C proteins in cells increased the fusion abilities in mitochondria and decreased their fission abilities relatively. The respective mutant proteins, but not wild type proteins also decreased the activities of mitochondria. While cells expressing the wild type proteins exhibited differentiated phenotypes with widespread membranes and increased expression levels of differentiation marker proteins following the induction of differentiation, cells harboring each of the mutant proteins did not. Taken together, these results indicate that an HLD10-associated PYCR2 mutation leads to the formation of large mitochondria with decreased activities, inhibiting oligodendroglial cell morphological differentiation. These results may reveal some of the pathological mechanisms in oligodendroglial cells underlying HLD10 at the molecular and cellular levels.https://www.mdpi.com/2035-8377/14/4/85HLD10PYCR2oligodendrocytedifferentiationmitochondrion |
| spellingShingle | Tomohiro Torii Remina Shirai Risa Kiminami Satoshi Nishino Takanari Sato Sui Sawaguchi Nana Fukushima Yoichi Seki Yuki Miyamoto Junji Yamauchi Hypomyelinating Leukodystrophy 10 (HLD10)-Associated Mutations of PYCR2 Form Large Size Mitochondria, Inhibiting Oligodendroglial Cell Morphological Differentiation Neurology International HLD10 PYCR2 oligodendrocyte differentiation mitochondrion |
| title | Hypomyelinating Leukodystrophy 10 (HLD10)-Associated Mutations of PYCR2 Form Large Size Mitochondria, Inhibiting Oligodendroglial Cell Morphological Differentiation |
| title_full | Hypomyelinating Leukodystrophy 10 (HLD10)-Associated Mutations of PYCR2 Form Large Size Mitochondria, Inhibiting Oligodendroglial Cell Morphological Differentiation |
| title_fullStr | Hypomyelinating Leukodystrophy 10 (HLD10)-Associated Mutations of PYCR2 Form Large Size Mitochondria, Inhibiting Oligodendroglial Cell Morphological Differentiation |
| title_full_unstemmed | Hypomyelinating Leukodystrophy 10 (HLD10)-Associated Mutations of PYCR2 Form Large Size Mitochondria, Inhibiting Oligodendroglial Cell Morphological Differentiation |
| title_short | Hypomyelinating Leukodystrophy 10 (HLD10)-Associated Mutations of PYCR2 Form Large Size Mitochondria, Inhibiting Oligodendroglial Cell Morphological Differentiation |
| title_sort | hypomyelinating leukodystrophy 10 hld10 associated mutations of pycr2 form large size mitochondria inhibiting oligodendroglial cell morphological differentiation |
| topic | HLD10 PYCR2 oligodendrocyte differentiation mitochondrion |
| url | https://www.mdpi.com/2035-8377/14/4/85 |
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