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Phosphodiesterase 7 Regulation in Cellular and Rodent Models of Parkinson’s Disease

Abstract

Parkinson’s disease is characterized by a loss of dopaminergic neurons in the ventral midbrain. This disease is diagnosed when around 50% of these neurons have already died; consequently, therapeutic treatments start too late. Therefore, an urgent need exists to find new targets involved in the onset and progression of the disease. Phosphodiesterase 7 (PDE7) is a key enzyme involved in the degradation of intracellular levels of cyclic adenosine 3′, 5′-monophosphate in different cell types; however, little is known regarding its role in neurodegenerative diseases, and specifically in Parkinson’s disease. We have previously shown that chemical as well as genetic inhibition of this enzyme results in neuroprotection and anti-inflammatory activity in different models of neurodegenerative disorders, including Parkinson’s disease. Here, we have used in vitro and in vivo models of Parkinson’s disease to study the regulation of PDE7 protein levels. Our results show that PDE7 is upregulated after an injury both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures and after lipopolysaccharide or 6-hidroxydopamine injection in the Substantia nigra pars compacta of adult mice. PDE7 increase takes place mainly in degenerating dopaminergic neurons and in microglia cells. This enhanced expression appears to be direct since 6-hydroxydopamine and lipopolysaccharide increase the expression of a 962-bp fragment of its promoter. Taking together, these results reveal an essential function for PDE7 in the pathways leading to neurodegeneration and inflammatory-mediated brain damage and suggest novel roles for PDE7 in neurodegenerative diseases, specifically in PD, opening the door for new therapeutic interventions.

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Abbreviations

6-OHDA:

6-Hydroxydopamine

AD:

Alzheimer’s disease

DAPI:

4′,6-Diamidino-2-phenylindole

GFAP:

Glial fibrillary acidic protein

LPS:

Lipopolysaccharide

PD:

Parkinson’s disease

PDEs:

Phosphodiesterases

PDE7:

Phosphodiesterase 7

SNpc:

Substantia nigra pars compacta

TH:

Tyrosine hydroxylase

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Acknowledgments

We thank Monica Belinchon, expert in confocal images, for her technical support with the confocal microscope and Victor Echeverry, Jose Antonio Lopez-Moreno and Manuel Guzman from the Complutense University for kindly providing us with DAT and DARPP32 antibodies.

Funding

This work was financially supported by the Spanish Ministry of Economy and Competitiveness (grants SAF2014-52940-R and SAF2017-85199-P to A.P-C) and partially financed with FEDER funds. The Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED) is funded by the Institute for Health “Carlos III.” J.A.M-G. is a post-doctoral fellow from CIBERNED.

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Correspondence to Jose A. Morales-Garcia or Ana Perez-Castillo.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All animal experiments were specifically approved by the “Ethics Committee for Animal Experimentation” of the Instituto de Investigaciones Biomedicas (CSIC-UAM) and carried out in accordance with the European Communities Council Directive (2010/63/EEC) and National regulations (normative 53/2013).

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Morales-Garcia, J.A., Alonso-Gil, S., Santos, Á. et al. Phosphodiesterase 7 Regulation in Cellular and Rodent Models of Parkinson’s Disease. Mol Neurobiol 57, 806–822 (2020). https://doi.org/10.1007/s12035-019-01745-z

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Keywords

  • Astrocytes
  • Microglial cells
  • Neurodegeneration
  • Neuroinflammation
  • Parkinson
  • Phosphodiesterase7
  • Regulation