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Link to original content: https://pubmed.ncbi.nlm.nih.gov/33026587/
Purinergic Receptors in Basal Ganglia Diseases: Shared Molecular Mechanisms between Huntington's and Parkinson's Disease - PubMed Skip to main page content
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Review
. 2020 Nov;36(11):1299-1314.
doi: 10.1007/s12264-020-00582-8. Epub 2020 Oct 7.

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

Talita Glaser  1 , Roberta Andrejew  1 , Ágatha Oliveira-Giacomelli  1 , Deidiane Elisa Ribeiro  1 , Lucas Bonfim Marques  1 , Qing Ye  1   2 , Wen-Jing Ren  2   3 , Alexey Semyanov  4   5 , Peter Illes  3   6 , Yong Tang  2   6 , Henning Ulrich  7
Affiliations
Review

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

Talita Glaser et al. Neurosci Bull. 2020 Nov.

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.

Keywords: 6-hydroxydopamine; Central nervous system; Huntington’s disease; Parkinson’s disease; Purinergic receptor.

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Conflict of interest statement

The authors claim that there are no conflict of interest.

Figures

Fig. 1
Fig. 1
Huntington’s and Parkinson’s disease characteristics.
Fig. 2
Fig. 2
Basal ganglia. A Locations of primary and secondary motor cortex. B Basal ganglia structures involved in the pathophysiology of HD and PD. C Neuronal network involved in the pathophysiology of HD and PD. Cortical glutamatergic excitatory neurons connect to inhibitory GABAergic neurons in the putamen, that innervate the SN and the GP. The direct pathway is regulated in the putamen by dopaminergic afferents exerting excitatory effects through D1 receptors, and the indirect pathway with inhibitory effects through D2 receptors. These receptors are modulated by A1 and A2A receptors, respectively.
Fig. 3
Fig. 3
Purinergic receptors and Ca2+ signaling as common mechanisms in PD and HD. A Schematic presentation of the corticostriatal and nigrostriatal pathways. The striatum is mainly composed of GABAergic medium spiny neurons that project to direct or indirect movement pathways. B, C Glutamate, dopamine, adenosine and ATP control the direct and indirect signaling pathways, depending on the formation of adenosinergic–dopaminergic receptor dimers. The direct pathway stimulates GABAergic medium spiny neurons expressing D1 excitatory receptors, that inhibit motor function when dimerized with the A1 receptor. C, D The indirect pathway stimulates GABAergic medium spiny neurons expressing D2 inhibitory receptors. When D2 receptors form complexes with A2A and mGlu5 receptors, these neurons are inhibited with consequent movement promotion. E In PD, the dopamine levels in synapses are diminished, favoring A2A receptor activity, which leads to PKA activation and the inhibition of movements, while increasing [Ca2+]i and the aggregation of α-synuclein. F In HD, P2X7 receptors mediate increased Ca2+ inflow, moving the cell towards apoptosis pathways through depolarization of mitochondrial membrane potential, the release of cytochrome c and the activation of caspases. Moreover, NMDA receptors interact with mHtt, presenting abnormal Ca2+ influx and leading to the same cell death pathways, including the formation of ROS. Abbreviations: NMDA, N-methyl-D-aspartate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; DARPP-32, dopamine- and cAMP-regulated neuronal phosphoprotein; MAPK, mitogen-activated protein kinase/extracellular signal-regulated kinase; CREB, cAMP response element-binding protein; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ΔΨ, change in membrane potential; ROS, reactive oxygen species; IP3R, inositol trisphosphate receptor; ER, endoplasmic reticulum; mHtt, mutant huntingtin protein.
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