| RRC ID |
33327
|
| 著者 |
Uemura N, Koike M, Ansai S, Kinoshita M, Ishikawa-Fujiwara T, Matsui H, Naruse K, Sakamoto N, Uchiyama Y, Todo T, Takeda S, Yamakado H, Takahashi R.
|
| タイトル |
Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein.
|
| ジャーナル |
PLoS Genet
|
| Abstract |
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.
|
| 巻・号 |
11(4)
|
| ページ |
e1005065
|
| 公開日 |
2015-4-1
|
| DOI |
10.1371/journal.pgen.1005065
|
| PII |
PGENETICS-D-14-03033
|
| PMID |
25835295
|
| PMC |
PMC4383526
|
| MeSH |
Animals
Axons / metabolism*
Axons / ultrastructure
Disease Models, Animal
Gaucher Disease / genetics*
Gaucher Disease / metabolism
Gaucher Disease / pathology
Glucosylceramidase / deficiency*
Glucosylceramidase / genetics
Oryzias / genetics*
Oryzias / metabolism
Phagosomes / metabolism
alpha-Synuclein / metabolism*
|
| IF |
5.175
|
| 引用数 |
32
|
|
WOS 分野
|
GENETICS & HEREDITY
|
| リソース情報 |
| メダカ |
TILLING_MUTANT
Kyoto-Cab (OK-Cab(MT830)) |
