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Advancing Parkinson’s disease biopathology and drug discovery by dual cellular modelling

Parkinson’s disease (PD) is the fastest growing neurological disorder in the world. Its pathologic hallmarks are dopaminergic neuronal loss in the substantia nigra and alpha-synuclein accumulation in neurons. However, the patho-biologic mechanisms are largely unknown. Current drugs cannot slow or...

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Main Authors: Chua, Pin Fen, Nurr Maria Ulfa, Seruji, Mas Atikah, Lizazman, Vivien Jong, Yi Mian, William K., Lim
Format: Article
Language:English
Published: Elsevier B.V. 2024
Subjects:
RM Therapeutics. Pharmacology
Online Access:http://ir.unimas.my/id/eprint/46846/3/Advancing%20Parkinson%E2%80%99s.pdf
http://ir.unimas.my/id/eprint/46846/
https://www.sciencedirect.com/science/article/pii/S1018364724004713
https://doi.org/10.1016/j.jksus.2024.103559
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spelling my.unimas.ir-468462024-12-09T04:59:53Z http://ir.unimas.my/id/eprint/46846/ Advancing Parkinson’s disease biopathology and drug discovery by dual cellular modelling Chua, Pin Fen Nurr Maria Ulfa, Seruji Mas Atikah, Lizazman Vivien Jong, Yi Mian William K., Lim RM Therapeutics. Pharmacology Parkinson’s disease (PD) is the fastest growing neurological disorder in the world. Its pathologic hallmarks are dopaminergic neuronal loss in the substantia nigra and alpha-synuclein accumulation in neurons. However, the patho-biologic mechanisms are largely unknown. Current drugs cannot slow or halt disease progression while clinical trials are mostly unsuccessful. Hence better cellular models are needed for pathological and drug dis covery studies prior to in vivo validation. PC12 cells are commonly used for neurotoxicity studies but the Neuroscreen-1 (NS-1) variant has a faster doubling time and higher basal rate of neurite growth. We developed a NS-1 PD model with the neurotoxin 6-hydroxydopamine (6-OHDA) and MTT cell viability assay as readout. We optimized 6-OHDA concentration to a uniquely low 10 µM for a closer approximation to in vivo neurotoxicity. NS1 cells treated with 6-OHDA displayed hallmark dopamine loss and apoptotic cell death. We used the model to screen a series of xanthones − polyphenolic compounds found in many medicinal plants. We report a novel activity of thwaitesixanthone in the PD model. The model was validated using alpha-mangostin (a neuro protectant in in vivo and in vitro PD models) which was the most active in restoring cell viability. Alpha-synuclein is now a therapeutic target for stopping PD progression. Human HEK293 cells have neuronal attributes and reported to express pathologic alpha-synuclein. We hypothesized the transfection-efficient HEK293T cells is an optimal cell line for monitoring human alpha-synuclein levels. We make the first report that 6-OHDA treatment increased pathologic alpha-synuclein expression in HEK293T cells. This alpha-synucleinopathy model was validated using alpha-mangostin which attenuated 6-OHDA-induced pathologic alpha-synuclein to baseline levels. Thus we developed a novel NS-1 PD model more representative of in vivo neurotoxicity complemented by a human HEK293T cell-based alpha-synucleinopathy model for tracking pathologic alpha-synuclein levels. We present these dual models for producing in vitro findings with increased likelihood of clinical translation. Elsevier B.V. 2024 Article PeerReviewed text en http://ir.unimas.my/id/eprint/46846/3/Advancing%20Parkinson%E2%80%99s.pdf Chua, Pin Fen and Nurr Maria Ulfa, Seruji and Mas Atikah, Lizazman and Vivien Jong, Yi Mian and William K., Lim (2024) Advancing Parkinson’s disease biopathology and drug discovery by dual cellular modelling. Journal of King Saud University - Science, 36 (11). pp. 1-8. ISSN 1018-3647 https://www.sciencedirect.com/science/article/pii/S1018364724004713 https://doi.org/10.1016/j.jksus.2024.103559
institution Universiti Malaysia Sarawak
building Centre for Academic Information Services (CAIS)
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaysia Sarawak
content_source UNIMAS Institutional Repository
url_provider http://ir.unimas.my/
language English
topic RM Therapeutics. Pharmacology
spellingShingle RM Therapeutics. Pharmacology
Chua, Pin Fen
Nurr Maria Ulfa, Seruji
Mas Atikah, Lizazman
Vivien Jong, Yi Mian
William K., Lim
Advancing Parkinson’s disease biopathology and drug discovery by dual cellular modelling
description Parkinson’s disease (PD) is the fastest growing neurological disorder in the world. Its pathologic hallmarks are dopaminergic neuronal loss in the substantia nigra and alpha-synuclein accumulation in neurons. However, the patho-biologic mechanisms are largely unknown. Current drugs cannot slow or halt disease progression while clinical trials are mostly unsuccessful. Hence better cellular models are needed for pathological and drug dis covery studies prior to in vivo validation. PC12 cells are commonly used for neurotoxicity studies but the Neuroscreen-1 (NS-1) variant has a faster doubling time and higher basal rate of neurite growth. We developed a NS-1 PD model with the neurotoxin 6-hydroxydopamine (6-OHDA) and MTT cell viability assay as readout. We optimized 6-OHDA concentration to a uniquely low 10 µM for a closer approximation to in vivo neurotoxicity. NS1 cells treated with 6-OHDA displayed hallmark dopamine loss and apoptotic cell death. We used the model to screen a series of xanthones − polyphenolic compounds found in many medicinal plants. We report a novel activity of thwaitesixanthone in the PD model. The model was validated using alpha-mangostin (a neuro protectant in in vivo and in vitro PD models) which was the most active in restoring cell viability. Alpha-synuclein is now a therapeutic target for stopping PD progression. Human HEK293 cells have neuronal attributes and reported to express pathologic alpha-synuclein. We hypothesized the transfection-efficient HEK293T cells is an optimal cell line for monitoring human alpha-synuclein levels. We make the first report that 6-OHDA treatment increased pathologic alpha-synuclein expression in HEK293T cells. This alpha-synucleinopathy model was validated using alpha-mangostin which attenuated 6-OHDA-induced pathologic alpha-synuclein to baseline levels. Thus we developed a novel NS-1 PD model more representative of in vivo neurotoxicity complemented by a human HEK293T cell-based alpha-synucleinopathy model for tracking pathologic alpha-synuclein levels. We present these dual models for producing in vitro findings with increased likelihood of clinical translation.
format Article
author Chua, Pin Fen
Nurr Maria Ulfa, Seruji
Mas Atikah, Lizazman
Vivien Jong, Yi Mian
William K., Lim
author_facet Chua, Pin Fen
Nurr Maria Ulfa, Seruji
Mas Atikah, Lizazman
Vivien Jong, Yi Mian
William K., Lim
author_sort Chua, Pin Fen
title Advancing Parkinson’s disease biopathology and drug discovery by dual cellular modelling
title_short Advancing Parkinson’s disease biopathology and drug discovery by dual cellular modelling
title_full Advancing Parkinson’s disease biopathology and drug discovery by dual cellular modelling
title_fullStr Advancing Parkinson’s disease biopathology and drug discovery by dual cellular modelling
title_full_unstemmed Advancing Parkinson’s disease biopathology and drug discovery by dual cellular modelling
title_sort advancing parkinson’s disease biopathology and drug discovery by dual cellular modelling
publisher Elsevier B.V.
publishDate 2024
url http://ir.unimas.my/id/eprint/46846/3/Advancing%20Parkinson%E2%80%99s.pdf
http://ir.unimas.my/id/eprint/46846/
https://www.sciencedirect.com/science/article/pii/S1018364724004713
https://doi.org/10.1016/j.jksus.2024.103559
_version_ 1818839387732967424
score 13.223943

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