The potential convergence of NLRP3 inflammasome, potassium, and dopamine mechanisms in Parkinson’s disease
Abstract The pathology of Parkinson’s disease (PD) is characterized by α-synuclein aggregation, microglia-mediated neuroinflammation, and dopaminergic neurodegeneration in the substantia nigra with collateral striatal dopamine signaling deficiency. Microglial NLRP3 inflammasome activation has been l...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-03-01
|
| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-022-00293-z |
| _version_ | 1797426558744395776 |
|---|---|
| author | Adrianne F. Pike Ildikò Szabò Robert Veerhuis Luigi Bubacco |
| author_facet | Adrianne F. Pike Ildikò Szabò Robert Veerhuis Luigi Bubacco |
| author_sort | Adrianne F. Pike |
| collection | DOAJ |
| description | Abstract The pathology of Parkinson’s disease (PD) is characterized by α-synuclein aggregation, microglia-mediated neuroinflammation, and dopaminergic neurodegeneration in the substantia nigra with collateral striatal dopamine signaling deficiency. Microglial NLRP3 inflammasome activation has been linked independently to each of these facets of PD pathology. The voltage-gated potassium channel Kv1.3, upregulated in microglia by α-synuclein and facilitating potassium efflux, has also been identified as a modulator of neuroinflammation and neurodegeneration in models of PD. Evidence increasingly suggests that microglial Kv1.3 is mechanistically coupled with NLRP3 inflammasome activation, which is contingent on potassium efflux. Potassium conductance also influences dopamine release from midbrain dopaminergic neurons. Dopamine, in turn, has been shown to inhibit NLRP3 inflammasome activation in microglia. In this review, we provide a literature framework for a hypothesis in which Kv1.3 activity-induced NLRP3 inflammasome activation, evoked by stimuli such as α-synuclein, could lead to microglia utilizing dopamine from adjacent dopaminergic neurons to counteract this process and fend off an activated state. If this is the case, a sufficient dopamine supply would ensure that microglia remain under control, but as dopamine is gradually siphoned from the neurons by microglial demand, NLRP3 inflammasome activation and Kv1.3 activity would progressively intensify to promote each of the three major facets of PD pathology: α-synuclein aggregation, microglia-mediated neuroinflammation, and dopaminergic neurodegeneration. Risk factors overlapping to varying degrees to render brain regions susceptible to such a mechanism would include a high density of microglia, an initially sufficient supply of dopamine, and poor insulation of the dopaminergic neurons by myelin. |
| first_indexed | 2024-03-09T08:31:58Z |
| format | Article |
| id | doaj.art-9ae3904e58f840f4b312ad9cd14c67d5 |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-03-09T08:31:58Z |
| publishDate | 2022-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-9ae3904e58f840f4b312ad9cd14c67d52023-12-02T19:41:46ZengNature Portfolionpj Parkinson's Disease2373-80572022-03-01811910.1038/s41531-022-00293-zThe potential convergence of NLRP3 inflammasome, potassium, and dopamine mechanisms in Parkinson’s diseaseAdrianne F. Pike0Ildikò Szabò1Robert Veerhuis2Luigi Bubacco3Amsterdam UMC, Vrije Universiteit Amsterdam, Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam NeuroscienceDepartment of Biology, University of PaduaAmsterdam UMC, Vrije Universiteit Amsterdam, Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam NeuroscienceDepartment of Biology, University of PaduaAbstract The pathology of Parkinson’s disease (PD) is characterized by α-synuclein aggregation, microglia-mediated neuroinflammation, and dopaminergic neurodegeneration in the substantia nigra with collateral striatal dopamine signaling deficiency. Microglial NLRP3 inflammasome activation has been linked independently to each of these facets of PD pathology. The voltage-gated potassium channel Kv1.3, upregulated in microglia by α-synuclein and facilitating potassium efflux, has also been identified as a modulator of neuroinflammation and neurodegeneration in models of PD. Evidence increasingly suggests that microglial Kv1.3 is mechanistically coupled with NLRP3 inflammasome activation, which is contingent on potassium efflux. Potassium conductance also influences dopamine release from midbrain dopaminergic neurons. Dopamine, in turn, has been shown to inhibit NLRP3 inflammasome activation in microglia. In this review, we provide a literature framework for a hypothesis in which Kv1.3 activity-induced NLRP3 inflammasome activation, evoked by stimuli such as α-synuclein, could lead to microglia utilizing dopamine from adjacent dopaminergic neurons to counteract this process and fend off an activated state. If this is the case, a sufficient dopamine supply would ensure that microglia remain under control, but as dopamine is gradually siphoned from the neurons by microglial demand, NLRP3 inflammasome activation and Kv1.3 activity would progressively intensify to promote each of the three major facets of PD pathology: α-synuclein aggregation, microglia-mediated neuroinflammation, and dopaminergic neurodegeneration. Risk factors overlapping to varying degrees to render brain regions susceptible to such a mechanism would include a high density of microglia, an initially sufficient supply of dopamine, and poor insulation of the dopaminergic neurons by myelin.https://doi.org/10.1038/s41531-022-00293-z |
| spellingShingle | Adrianne F. Pike Ildikò Szabò Robert Veerhuis Luigi Bubacco The potential convergence of NLRP3 inflammasome, potassium, and dopamine mechanisms in Parkinson’s disease npj Parkinson's Disease |
| title | The potential convergence of NLRP3 inflammasome, potassium, and dopamine mechanisms in Parkinson’s disease |
| title_full | The potential convergence of NLRP3 inflammasome, potassium, and dopamine mechanisms in Parkinson’s disease |
| title_fullStr | The potential convergence of NLRP3 inflammasome, potassium, and dopamine mechanisms in Parkinson’s disease |
| title_full_unstemmed | The potential convergence of NLRP3 inflammasome, potassium, and dopamine mechanisms in Parkinson’s disease |
| title_short | The potential convergence of NLRP3 inflammasome, potassium, and dopamine mechanisms in Parkinson’s disease |
| title_sort | potential convergence of nlrp3 inflammasome potassium and dopamine mechanisms in parkinson s disease |
| url | https://doi.org/10.1038/s41531-022-00293-z |
| work_keys_str_mv | AT adriannefpike thepotentialconvergenceofnlrp3inflammasomepotassiumanddopaminemechanismsinparkinsonsdisease AT ildikoszabo thepotentialconvergenceofnlrp3inflammasomepotassiumanddopaminemechanismsinparkinsonsdisease AT robertveerhuis thepotentialconvergenceofnlrp3inflammasomepotassiumanddopaminemechanismsinparkinsonsdisease AT luigibubacco thepotentialconvergenceofnlrp3inflammasomepotassiumanddopaminemechanismsinparkinsonsdisease AT adriannefpike potentialconvergenceofnlrp3inflammasomepotassiumanddopaminemechanismsinparkinsonsdisease AT ildikoszabo potentialconvergenceofnlrp3inflammasomepotassiumanddopaminemechanismsinparkinsonsdisease AT robertveerhuis potentialconvergenceofnlrp3inflammasomepotassiumanddopaminemechanismsinparkinsonsdisease AT luigibubacco potentialconvergenceofnlrp3inflammasomepotassiumanddopaminemechanismsinparkinsonsdisease |