Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein.
Homozygous mutations in the glucocerebrosidase (GBA) gene result in Gaucher disease (GD), the most common lysosomal storage disease. Recent genetic studies have revealed that GBA mutations confer a strong risk for sporadic Parkinson's disease (PD). To investigate how GBA mutations cause PD, we...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-04-01
|
| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC4383526?pdf=render |
| _version_ | 1828736134023217152 |
|---|---|
| author | Norihito Uemura Masato Koike Satoshi Ansai Masato Kinoshita Tomoko Ishikawa-Fujiwara Hideaki Matsui Kiyoshi Naruse Naoaki Sakamoto Yasuo Uchiyama Takeshi Todo Shunichi Takeda Hodaka Yamakado Ryosuke Takahashi |
| author_facet | Norihito Uemura Masato Koike Satoshi Ansai Masato Kinoshita Tomoko Ishikawa-Fujiwara Hideaki Matsui Kiyoshi Naruse Naoaki Sakamoto Yasuo Uchiyama Takeshi Todo Shunichi Takeda Hodaka Yamakado Ryosuke Takahashi |
| author_sort | Norihito Uemura |
| collection | DOAJ |
| description | Homozygous mutations in the glucocerebrosidase (GBA) gene result in Gaucher disease (GD), the most common lysosomal storage disease. Recent genetic studies have revealed that GBA mutations confer a strong risk for sporadic Parkinson's disease (PD). To investigate how GBA mutations cause PD, we generated GBA nonsense mutant (GBA-/-) medaka that are completely deficient in glucocerebrosidase (GCase) activity. In contrast to the perinatal death in humans and mice lacking GCase activity, GBA-/- medaka survived for months, enabling analysis of the pathological progression. GBA-/- medaka displayed the pathological phenotypes resembling human neuronopathic GD including infiltration of Gaucher cell-like cells into the brains, progressive neuronal loss, and microgliosis. Detailed pathological findings represented lysosomal abnormalities in neurons and alpha-synuclein (α-syn) accumulation in axonal swellings containing autophagosomes. Unexpectedly, disruption of α-syn did not improve the life span, formation of axonal swellings, neuronal loss, or neuroinflammation in GBA-/- medaka. Taken together, the present study revealed GBA-/- medaka as a novel neuronopathic GD model, the pahological mechanisms of α-syn accumulation caused by GCase deficiency, and the minimal contribution of α-syn to the pathogenesis of neuronopathic GD. |
| first_indexed | 2024-04-12T23:19:54Z |
| format | Article |
| id | doaj.art-d707126108e9415198b5a43c86b96048 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-12T23:19:54Z |
| publishDate | 2015-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-d707126108e9415198b5a43c86b960482022-12-22T03:12:34ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042015-04-01114e100506510.1371/journal.pgen.1005065Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein.Norihito UemuraMasato KoikeSatoshi AnsaiMasato KinoshitaTomoko Ishikawa-FujiwaraHideaki MatsuiKiyoshi NaruseNaoaki SakamotoYasuo UchiyamaTakeshi TodoShunichi TakedaHodaka YamakadoRyosuke TakahashiHomozygous mutations in the glucocerebrosidase (GBA) gene result in Gaucher disease (GD), the most common lysosomal storage disease. Recent genetic studies have revealed that GBA mutations confer a strong risk for sporadic Parkinson's disease (PD). To investigate how GBA mutations cause PD, we generated GBA nonsense mutant (GBA-/-) medaka that are completely deficient in glucocerebrosidase (GCase) activity. In contrast to the perinatal death in humans and mice lacking GCase activity, GBA-/- medaka survived for months, enabling analysis of the pathological progression. GBA-/- medaka displayed the pathological phenotypes resembling human neuronopathic GD including infiltration of Gaucher cell-like cells into the brains, progressive neuronal loss, and microgliosis. Detailed pathological findings represented lysosomal abnormalities in neurons and alpha-synuclein (α-syn) accumulation in axonal swellings containing autophagosomes. Unexpectedly, disruption of α-syn did not improve the life span, formation of axonal swellings, neuronal loss, or neuroinflammation in GBA-/- medaka. Taken together, the present study revealed GBA-/- medaka as a novel neuronopathic GD model, the pahological mechanisms of α-syn accumulation caused by GCase deficiency, and the minimal contribution of α-syn to the pathogenesis of neuronopathic GD.http://europepmc.org/articles/PMC4383526?pdf=render |
| spellingShingle | Norihito Uemura Masato Koike Satoshi Ansai Masato Kinoshita Tomoko Ishikawa-Fujiwara Hideaki Matsui Kiyoshi Naruse Naoaki Sakamoto Yasuo Uchiyama Takeshi Todo Shunichi Takeda Hodaka Yamakado Ryosuke Takahashi Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein. PLoS Genetics |
| title | Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein. |
| title_full | Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein. |
| title_fullStr | Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein. |
| title_full_unstemmed | Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein. |
| title_short | Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein. |
| title_sort | viable neuronopathic gaucher disease model in medaka oryzias latipes displays axonal accumulation of alpha synuclein |
| url | http://europepmc.org/articles/PMC4383526?pdf=render |
| work_keys_str_mv | AT norihitouemura viableneuronopathicgaucherdiseasemodelinmedakaoryziaslatipesdisplaysaxonalaccumulationofalphasynuclein AT masatokoike viableneuronopathicgaucherdiseasemodelinmedakaoryziaslatipesdisplaysaxonalaccumulationofalphasynuclein AT satoshiansai viableneuronopathicgaucherdiseasemodelinmedakaoryziaslatipesdisplaysaxonalaccumulationofalphasynuclein AT masatokinoshita viableneuronopathicgaucherdiseasemodelinmedakaoryziaslatipesdisplaysaxonalaccumulationofalphasynuclein AT tomokoishikawafujiwara viableneuronopathicgaucherdiseasemodelinmedakaoryziaslatipesdisplaysaxonalaccumulationofalphasynuclein AT hideakimatsui viableneuronopathicgaucherdiseasemodelinmedakaoryziaslatipesdisplaysaxonalaccumulationofalphasynuclein AT kiyoshinaruse viableneuronopathicgaucherdiseasemodelinmedakaoryziaslatipesdisplaysaxonalaccumulationofalphasynuclein AT naoakisakamoto viableneuronopathicgaucherdiseasemodelinmedakaoryziaslatipesdisplaysaxonalaccumulationofalphasynuclein AT yasuouchiyama viableneuronopathicgaucherdiseasemodelinmedakaoryziaslatipesdisplaysaxonalaccumulationofalphasynuclein AT takeshitodo viableneuronopathicgaucherdiseasemodelinmedakaoryziaslatipesdisplaysaxonalaccumulationofalphasynuclein AT shunichitakeda viableneuronopathicgaucherdiseasemodelinmedakaoryziaslatipesdisplaysaxonalaccumulationofalphasynuclein AT hodakayamakado viableneuronopathicgaucherdiseasemodelinmedakaoryziaslatipesdisplaysaxonalaccumulationofalphasynuclein AT ryosuketakahashi viableneuronopathicgaucherdiseasemodelinmedakaoryziaslatipesdisplaysaxonalaccumulationofalphasynuclein |