MDS 18th International Congress of Parkinson's Disease and Movement Disorders, Volume 29, June 2014 Abstract SupplementMovement Disorders 2014Stockholm, Sweden June 8-12, 2014.

Human HtrA2 functions differently from drosophila HtrA2 in the detoxification of α-synuclein-induced neurotoxicity in a drosophila model of Parkinson's disease

Rahman,  M.M., Akhter,  Saidul Islam,  M.S., Kim,  H.-J., Hong,  S.-T.

Jessore, Bangladesh

Objective: To investigate the beneficial effects of human HtrA2 (hHtrA2) on the neurological phenotypes of Drosophila PD model.

Background: One of the most contentious debates in biological science concerns the role of HtrA2 in the pathogenesis of Parkinson's disease (PD). Although based on in vitro studies HtrA2 was proposed to be a pro-apoptotic protein, in vivo animal experiments showed that HtrA2 is dispensable for apoptosis and functions as a neuroprotective protein that prevents PD. HtrA2

has a high homology with bacterial heat shock protein, HtrA that protects bacterial cells from misfolded proteins-induced toxicity.

Methods: We directed the pan-neuronal expressions of wild-type α-synuclein (α-syn) to generate PD Drosophila model, hHtrA2 and dHtrA2 over expression fly's models, and co-expressions of wild-type α-syn with hHtrA2 or dHtrA2 to generate the PD rescue fly's models. To clarify the physiological function of hHtrA2 and dHtrA2 themselves and their ability to protect against α-syn-induced neurotoxicity, we performed longevity, mobility, immunochemical, immunohistochemical, light and confocal microscopy studies.

Results: Alpha-synuclein over expression causes abnormal accumulation of α-syn into aggregates called Lewy bodies, reduced lifespan, locomotor deficit and rough eyes in 30-60-days-old α-syn transgenic fly which indicates a toxic dominant mechanism of α-syn for the pathogenesis of PD. Overexpression of dHtrA2 alone resulted in a loss of eye pigmentation, reduced lifespan, locomotor dysfunction and male sterility indicating the cellular toxic effects of dHtrA2 but its toxicity is attenuated when co-expressed with α-syn. In contrast, hHtrA2 over expression alone improved the locomotion and longevity of the fly without losing the male fertility. Upon co-expression, hHtrA2 completely detoxified α-syn-induced neurotoxicity by degrading accumulated α-syn results in the rescue of the α-syn-induced phenotype of premature loss of climbing ability, longevity and developmental defects in the fly eye.

Conclusions: Our findings demonstrated the novel insight into the detoxification pathway of intraneuronal accumulated α-syn in a Drosophila model of PD without altering normal physiology of the fly suggesting the neuroprotective role of hHtrA2 is unique which is not analogous to dHtrA2.

To cite this abstract, please use the following information:Rahman, M.M., Akhter, S., Islam, M.S., Kim, H.-J., Hong, S.-T.; Human HtrA2 functions differently from drosophila HtrA2 in the detoxification of α-synuclein-induced neurotoxicity in a drosophila model of Parkinson's disease [abstract]. Movement Disorders 2014;29 Suppl 1 :602

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