Purinergic Receptors in Basal Ganglia Diseases: Shared Molecular Mechanisms between Huntington’s and Parkinson’s Disease

Abstract

Huntington’s (HD) and Parkinson’s diseases (PD) are neurodegenerative disorders caused by the death of GABAergic and dopaminergic neurons in the basal ganglia leading to hyperkinetic and hypokinetic symptoms, respectively. We review here the participation of purinergic receptors through intracellular Ca2+ signaling in these neurodegenerative diseases. The adenosine A2A receptor stimulates striatopallidal GABAergic neurons, resulting in inhibitory actions on GABAergic neurons of the globus pallidus. A2A and dopamine D2 receptors form functional heteromeric complexes inducing allosteric inhibition, and A2A receptor activation results in motor inhibition. Furthermore, the A2A receptor physically and functionally interacts with glutamate receptors, mainly with the mGlu5 receptor subtype. This interaction facilitates glutamate release, resulting in NMDA glutamate receptor activation and an increase of Ca2+ influx. P2X7 receptor activation also promotes glutamate release and neuronal damage. Thus, modulation of purinergic receptor activity, such as A2A and P2X7 receptors, and subsequent aberrant Ca2+ signaling, might present interesting therapeutic potential for HD and PD.

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Acknowledgements

This review was supported by the São Paulo Research Foundation (FAPESP; 2018/07366-4) and a Fellowship from the National Council for Scientific and Technological Development (CNPq; 306392/2017-8). TG, AOG, and DER are grateful for postdoctoral fellowships from FAPESP (2015/13345-1, 2019/26852-0, and 2018/17504-5). RA is grateful for a doctoral fellowship from FAPESP (2019/24553-5). LBM is thankful for a master fellowship from CNPq (133396/2019-3). QY is grateful for the fellowship from National Key R&D Program of China (2019YFC1709101), The Project First-Class Disciplines Development (CZYHW1901) of Chengdu University of TCM and Sichuan Science and Technology Program (2019YFH0108, 2018SZ0257). AS work was supported by Russian Science Foundation grant 20-14-00241. Figures were created with BioRender.com.

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Glaser, T., Andrejew, R., Oliveira-Giacomelli, Á. et al. Purinergic Receptors in Basal Ganglia Diseases: Shared Molecular Mechanisms between Huntington’s and Parkinson’s Disease. Neurosci. Bull. (2020). https://doi.org/10.1007/s12264-020-00582-8

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Keywords

  • Purinergic receptor
  • Central nervous system
  • Huntington’s disease
  • Parkinson’s disease
  • 6-hydroxydopamine