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Parkinson's Disease and Related Disorders

開催日 2014/9/11
時間 11:00 - 12:00
会場 Poster / Exhibition(Event Hall B)

Transgenic flies expressing dementia with Lewy bodies-linked human β-Synuclein exhibit neurodegenerative phenotypes

  • P1-301
  • 高松 芳樹 / Yoshiki Takamatsu:1 関山 一成 / Kazunari Sekiyama:1 本多 芳子 / Yoshiko Honda:2 児玉 亨 / Tohru Kodama:2 橋本 款 / Makoto Hashimoto:1 
  • 1:都医学研パーキンソン病 / Parkinson PJ, Tokyo Metropol Inst Med Sci, Tokyo, Japan 2:都医学研睡眠 / Sleep PJ, Tokyo Metropol Inst Med Sci, Tokyo, Japan 

β-Synuclein (βS), a non-amyloidogenic homologue of α-synuclein (αS), is a natural inhibitor of α synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Two missense mutations, P123H and V70M, have been identified to date in DLB patients. However the mechanisms by which these mutations stimulate neurodegeneration are unclear. Although mutations did not found in the αS gene of the P123H βS patient, anti-αS immunoreactive Lewy body pathology was observed in the brain section of the proband whereas no anti-βS immunoreactive aggregates were detectable. One possibility of the neurotoxic mechanism might be a loss of protective function of βS against αS. Alternatively, mutant βSs might be themselves pathogenic, since it has been reported that neurotoxic effects of αS were more accelerated when αS was co-expressed with mutant βSs than αS alone.
To better understand the neurodegenerative mechanisms by βS mutations, the present study was carried out.
Taking advantage of absence of endogenous synuclein, we generated transgenic fly. The UAS vectors containing wild type (WT) or mutants of human αS or βS (αS; WT or A53T, βS; WT, P123H, or V70M) were introduced into the same genomic position in the fly respectively, for the direct comparison of their functional properties as phenotypes of whole-organism.
Interestingly, when the transgene was expressed in dopaminergic neurons with ple-GAL4 driver, the lifespan and dopamine level were significantly reduced in flies of αS A53T and βS V70M as compared with their WT controls but no difference was observed between those of βS P123H and βS WT. Further supporting the neurodegenerative phenotype of the βS V70M, only αS A53T and βS V70M exhibited homozygote sterile when the transgene was expressed in the entire neuron using elav-GAL4 driver.
These results suggest that βS V70M is neurodegenerative similar to αS A53T. Analysis of combined effect of αSs and βSs are now in the process.

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