Papers

International journal
Dec, 2020

Degeneration of dopaminergic neurons and impaired intracellular trafficking in Atp13a2 deficient zebrafish.

IBRO reports
  • Hiromi Nyuzuki
  • ,
  • Shinji Ito
  • ,
  • Keisuke Nagasaki
  • ,
  • Yohei Nitta
  • ,
  • Noriko Matsui
  • ,
  • Akihiko Saitoh
  • ,
  • Hideaki Matsui

Volume
9
Number
First page
1
Last page
8
Language
English
Publishing type
Research paper (scientific journal)
DOI
10.1016/j.ibror.2020.05.002

ATP13A2 is the autosomal recessive causative gene for juvenile-onset Parkinson's disease (PARK9, Parkinson's disease 9), also known as Kufor-Rakeb syndrome. The disease is characterized by levodopa-responsive Parkinsonism, supranuclear gaze palsy, spasticity, and dementia. Previously, we have reported that Atp13a2 deficient medaka fish showed dopaminergic neurodegeneration and lysosomal dysfunction, indicating that lysosome-autophagy impairment might be one of the key pathogeneses of Parkinson's disease. Here, we established Atp13a2 deficient zebrafish using CRISPR/Cas9 gene editing. We found that the number of TH + neurons in the posterior tuberculum and the locus coeruleus significantly reduced (dopaminergic neurons, 64 % at 4 months and 37 % at 12 months, p < 0.001 and p < 0.05, respectively; norepinephrine neurons, 52 % at 4 months and 40 % at 12 months, p < 0.001 and p < 0.05, respectively) in Atp13a2 deficient zebrafish, proving the degeneration of dopaminergic neurons. In addition, we found the reduction (60 %, p < 0.05) of cathepsin D protein expression in Atp13a2 deficient zebrafish using immunoblot. Transmission electron microscopy analysis using middle diencephalon samples from Atp13a2 deficient zebrafish showed lysosome-like bodies with vesicle accumulation and fingerprint-like structures, suggesting lysosomal dysfunction. Furthermore, a significant reduction (p < 0.001) in protein expression annotated with vesicle fusion with Golgi apparatus in Atp13a2 deficient zebrafish by liquid-chromatography tandem mass spectrometry suggested intracellular trafficking impairment. Therefore, we concluded that Atp13a2 deficient zebrafish exhibited degeneration of dopaminergic neurons, lysosomal dysfunction and the possibility of intracellular trafficking impairment, which would be the key pathogenic mechanism underlying Parkinson's disease.

Link information
DOI
https://doi.org/10.1016/j.ibror.2020.05.002
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32529115
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283103
ID information
  • DOI : 10.1016/j.ibror.2020.05.002
  • Pubmed ID : 32529115
  • Pubmed Central ID : PMC7283103

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