Objective: Our study aims to delineate the role of HIF1α in a SH-SY5Y model of Parkinson’s disease (PD)
Background: Parkinson’s disease (PD) is one of the most common neurodegenerative movement disorders affecting up to 10 million people worldwide . Oxidative stress, along with a cascade of other cellular events, has been shown to be a major contributor to many of the hallmarks of idiopathic PD . A central cellular actor in response to oxidative stress is hypoxia-inducible factor 1 alpha (HIF1α) which is involved in many disease states, including PD. HIF1α is activated in PD conditions and has been shown to stabilize tyrosine hydroxylase – an enzyme involved in dopamine synthesis. In addition, neuroprotective effects of HIF1α have been reported . In this study, we aim to further elucidate the functional role of HIF1α on neuronal cell death associated with PD.
Method: HIF1α, proliferating cell nuclear antigen (PCNA) and caspase 3 (Casp3) were measured at RNA (quantitative PCR) and protein levels (western blot and immunofluorescence) in SH-SY5Y cells following:
1) 2mM MPP+ treatment
2) 2mM MPP+ and cobalt chloride (CoCl2, a chemical inducer of HIF1α) treatment
3) 2mM MPP+ treatment and HIF1α silencing using small interfering RNA (siRNA)
Results: Using PCR, western blot and immunofluorescence, we observed in six independent experiments that:
1. MPP+ treatment led to a significant increase in HIF1α expression levels and apoptosis marker Casp3, while tending to decrease expression levels of the proliferation marker PCNA
2. Combined MPP and CoCl2 treatment significantly increased Casp3 expression and reduced PCNA expression
3. Silencing of HIF1α with siRNA blunted the activation of Casp3 induced by MPP+ treatment and increased proliferation.
Conclusion: Previous studies support a neuroprotective role of HIF1α in PD. The present study challenges this concept and sheds light on the poorly understood role of HIF1α in PD. Our results show that silencing of HIF1α was able to significantly reduce MPP+-induced apoptosis and led to an increase in cell proliferation. Overall, our results suggest that HIF1α could elicit neurodegenerative effects in PD. In light of the necessity to find novel drugs to treat PD, deepening our knowledge of the mechanisms leading to neurodegeneration is timely and needs further investigation.
References: 1. Collaborators, G.B.D.P.s.D., Global, regional, and national burden of Parkinson’s disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol, 2018. 17(11): p. 939-953. 2. Hwang, O., Role of oxidative stress in Parkinson’s disease. Exp Neurobiol, 2013. 22(1): p. 11-7. 3. Lim, J., et al., Hypoxia-inducible factor-1alpha upregulates tyrosine hydroxylase and dopamine transporter by nuclear receptor ERRgamma in SH-SY5Y cells. Neuroreport, 2015. 26(6): p. 380-6.
To cite this abstract in AMA style:S. Acharya, A. Lumley, C. Mebarki, V. Stopa, M. Vausort, Y. Devaux. Silencing of hypoxia-inducible factor 1 alpha provokes a neuroprotective response in a SH-SY5Y model of Parkinson’s Disease. [abstract]. Mov Disord. 2021; 36 (suppl 1). https://www.mdsabstracts.org/abstract/silencing-of-hypoxia-inducible-factor-1-alpha-provokes-a-neuroprotective-response-in-a-sh-sy5y-model-of-parkinsons-disease/. Accessed November 29, 2023.
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