Glucocerebrosidase 1 deficient Danio rerio mirror key pathological aspects of human Gaucher disease and provide evidence of early microglial activation preceding alpha-synuclein-independent neuronal cell death

被引：91

作者：

Keatinge, Marcus ^{[1
,2
]}

Bui, Hai ^{[4
]}

Menke, Aswin ^{[5
]}

Chen, Yu-Chia ^{[6
,7
]}

Sokol, Anna M. ^{[8
]}

Bai, Qing ^{[9
,10
]}

Ellett, Felix ^{[1
]}

Da Costa, Marc ^{[1
,2
]}

Burke, Derek ^{[11
,12
,13
]}

Gegg, Matthew ^{[14
]}

Trollope, Lisa ^{[1
,2
]}

Payne, Thomas ^{[1
,2
]}

McTighe, Aimee ^{[1
,2
]}

Mortiboys, Heather ^{[2
]}

de Jager, Sarah ^{[15
]}

Nuthall, Hugh ^{[4
]}

Kuo, Ming-Shang ^{[4
]}

Fleming, Angeleen ^{[15
]}

Schapira, Anthony H. V. ^{[14
]}

Renshaw, Stephen A. ^{[1
,3
]}

Highley, J. Robin ^{[2
]}

Chacinska, Agnieszka ^{[8
]}

Panula, Pertti ^{[6
,7
]}

Burton, Edward A. ^{[9
,10
]}

O'Neill, Michael J. ^{[16
]}

Bandmann, Oliver ^{[1
,2
]}

机构：

[1] Univ Sheffield, Bateson Ctr, Sheffield S10 2HQ, S Yorkshire, England

[2] Univ Sheffield, Sheffield Inst Translat Neurosci SITraN, Sheffield S10 2HQ, S Yorkshire, England

[3] Univ Sheffield, Dept Infect & Immun, Sheffield S10 2HQ, S Yorkshire, England

[4] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA

[5] TNO, NL-3700 AJ Zeist, Netherlands

[6] Univ Helsinki, Neurosci Ctr, FIN-00014 Helsinki, Finland

[7] Univ Helsinki, Dept Anat, FIN-00014 Helsinki, Finland

[8] Int Inst Mol & Cell Biol, Lab Mitochondrial Biogenesis, Warsaw, Poland

[9] Univ Pittsburgh, Sch Med, Pittsburgh Inst Neurodegenerat Dis, Pittsburgh, PA USA

[10] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA

[11] UCL, Inst Child Hlth, Mol & Genet Unit, London, England

[12] Great Ormond St Hosp Sick Children, Enzyme Unit, London, England

[13] Great Ormond St Hosp Sick Children, Metab Unit, Chem Pathol, London, England

[14] UCL, Inst Neurol, Dept Clin Neurosci, London, England

[15] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Cambridge, England

[16] Eli Lilly & Co Ltd, Surrey, England

来源：

HUMAN MOLECULAR GENETICS | 2015年 / 24卷 / 23期

基金：

英国惠康基金; 英国生物技术与生命科学研究理事会; 澳大利亚国家健康与医学研究理事会; 芬兰科学院;

关键词：

PARKINSONS-DISEASE; MOUSE MODEL; DOPAMINERGIC SYSTEM; LARVAL ZEBRAFISH; COMPLEX-I; MUTATIONS; BRAIN; NEURODEGENERATION; MIR-155; ACCUMULATION;

D O I：

10.1093/hmg/ddv369

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Autosomal recessively inherited glucocerebrosidase 1 (GBA1) mutations cause the lysosomal storage disorder Gaucher's disease (GD). Heterozygous GBA1 mutations (GBA1(+/-)) are the most common risk factor for Parkinson's disease (PD). Previous studies typically focused on the interaction between the reduction of glucocerebrosidase (enzymatic) activity in GBA1(+/-) carriers and alpha-synuclein-mediated neurotoxicity. However, it is unclear whether other mechanisms also contribute to the increased risk of PD in GBA1(+/-) carriers. The zebrafish genome does not contain alpha-synuclein (SNCA), thus providing a unique opportunity to study pathogenic mechanisms unrelated to alpha-synuclein toxicity. Here we describe a mutant zebrafish line created by TALEN genome editing carrying a 23 bp deletion in gba1 (gba1(c.1276_1298del)), the zebrafish orthologue of human GBA1. Marked sphingolipid accumulation was already detected at 5 days post-fertilization with accompanying microglial activation and early, sustained up-regulation of miR-155, a master regulator of inflammation. gba1c.1276_1298del mutant zebrafish developed a rapidly worsening phenotype from 8 weeks onwards with striking reduction in motor activity by 12 weeks. Histopathologically, we observed marked Gaucher cell invasion of the brain and other organs. Dopaminergic neuronal cell count was normal through development but reduced by >30% at 12 weeks in the presence of ubiquitin-positive, intra-neuronal inclusions. This gba1c.1276_1298del zebrafish line is the first viable vertebrate model sharing key pathological features of GD in both neuronal and non-neuronal tissue. Our study also provides evidence for early microglial activation prior to alpha-synuclein independent neuronal cell death in GBA1 deficiency and suggests upregulation of miR-155 as a common denominator across different neurodegenerative disorders.

引用

页码：6640 / 6652

页数：13