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ZEBRAFISH AS A MODEL OF GLUCOCEREBROSIDASE 1 (GBA1) DEFICIENCY
  1. Marcus Keatinge1,
  2. Marc DaCosta1,
  3. Aswin Menke2,
  4. Yu-Chia Chen3,
  5. Hai Hoang Bui4,
  6. Mike O'Neill5,
  7. Oliver Bandmann1
  1. 1University of Sheffield
  2. 3TNO, Triskelion, Holland
  3. 4University of Helsinki, Finnland
  4. 5Eli-Lilly, USA
  5. 6Eli-Lilly, UK

Abstract

Objectives To establish and characterise glucocerebrosidase 1 (GBA1) mutant zebrafish line.

Background Homozygous GBA1 mutations (GBA1−/−) cause Gaucher disease (GD), heterozygote GBA1 mutations (GBA+/−) are the most common risk factor for Parkinson's disease (PD). The aim of this project was to develop a zebrafish model of GBA1 deficiency and study PD-relevant mechanisms.

Methods Genome editing, RT PCR, behavioural analysis, Immunohistochemistry, H/E staining, in situ hybridisation, biochemical assays.

Results Homozygous mutants (GBA1−/−) developed normally and did not experience dopaminergic (DA) cell loss during development but displayed loss of DA neurons at 12 weeks. Video tracking revealed a large decrease in spontaneous movements in GBA1−/− compared to WT and an intermediate motor phenotype in GBA1+/− in juvenile zebrafish. All homozygous mutants had to be culled at 3 months of age due to the severity of the phenotype. Established GD biomarkers such as hexosaminidase or chitotriosidase activity were markedly abnormal (p<0.0001). Furthermore, there was marked impairment of mitochondrial respiratory chain activity in GBA−/−.

Conclusions GBA1−/− zebrafish share key biochemical and morphological features with GBA1 knockout mice or indeed human GD. This new vertebrate model system for GBA1 deficiency will be useful to study the interaction between GBA1 haploinsufficiency, alpha-synuclein and exogenous toxins.

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