Neuronal DAMPs exacerbate neurodegeneration via astrocytic RIPK3 signaling

JCI Insight, Journal Year: 2024, Volume and Issue: 9(11)

Published: May 7, 2024

Astrocyte activation is a common feature of neurodegenerative diseases. However, the ways in which dying neurons influence activity astrocytes poorly understood. Receptor interacting protein kinase-3 (RIPK3) signaling has recently been described as key regulator neuroinflammation, but whether this kinase mediates astrocytic responsiveness to neuronal death not yet studied. Here, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model Parkinson's disease show that RIPK3 drives dopaminergic cell and axon damage. Transcriptomic profiling revealed promoted gene expression associated with neuroinflammation movement disorders, coincided significant engagement damage molecular pattern (DAMP) signaling. In mechanistic experiments, factors released from signal through receptor for advanced glycation endproducts (RAGE) induce signaling, conferred inflammatory neurotoxic functional activity. These findings highlight mechanism neuron-glia crosstalk perpetuates further neurodegeneration by engaging astrocyte via RIPK3.

Language: Английский

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Incentive Cocaine‐Seeking Habits and Their Compulsive Manifestation Emerge After a Downregulation of the Dopamine Transporter in Astrocytes Across Functional Domains of the Striatum

European Journal of Neuroscience, Journal Year: 2025, Volume and Issue: 61(5)

Published: March 1, 2025

ABSTRACT The development of compulsive cue‐controlled‐incentive drug‐seeking habits is a hallmark substance use disorder that predicated on an intrastriatal shift in the locus control over behaviour from nucleus accumbens (Nac) core–dorsomedial striatum network to Nac core–anterior dorsolateral (aDLS) network. This paralleled by drug‐induced (including cocaine) dopamine transporter (DAT) alterations originating ventral spread eventually encompass aDLS. Having recently shown heroin self‐administration results pan‐striatal reduction astrocytic DAT precedes aDLS dopamine‐dependent incentive heroin‐seeking habits, we tested hypothesis similar adaptations occur following cocaine exposure. We compared protein levels whole tissue homogenates, and astrocytes cultured dorsal striatal territories drug‐naïve male Sprague–Dawley rats those with history taking or cocaine‐seeking habit. Cocaine exposure resulted decrease across all striatum. further demonstrated (i.e., punishment‐resistant) were associated mRNA shell, but not core‐aDLS habit system. Together recent evidence heroin‐induced downregulation DAT, these findings suggest may represent common mechanism underlying drug classes.

Language: Английский

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Dopamine transporter endocytic trafficking: Neuronal mechanisms and potential impact on DA‐dependent behaviors

Journal of Neurochemistry, Journal Year: 2024, Volume and Issue: 169(1)

Published: Dec. 10, 2024

Abstract The dopamine (DA) transporter (DAT) is a major determinant of DAergic neurotransmission, and primary target for addictive therapeutic psychostimulants. Evidence accumulated over decades in cell lines vitro preparations revealed that DAT function acutely regulated by membrane trafficking. Many these findings have recently been validated vivo situ, several behavioral physiological raise the possibility trafficking may impact DA signaling DA‐dependent behaviors. Here we review key across multiple systems, discuss cellular mechanisms mediate trafficking, as well endogenous receptors pathways drive We additionally recent dysfunction correlates to perturbations image

Language: Английский

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Parkinson’s disease gene, Synaptojanin1, dysregulates the basal maintenance of the dopamine transporter

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: March 13, 2024

Missense mutations of PARK20/SYNJ1 (synaptojanin1/Synj1) have been linked to complex forms familial parkinsonism, however, the molecular and cellular changes associated with dopaminergic dysfunction remains unknown. We now report fast depletion evoked dopamine (DA) altered maintenance axonal transporter (DAT) in Synj1+/- neurons. While Synj1 has traditionally known facilitate endocytosis synaptic vesicles, we demonstrated that axons cultured neurons exhibit an increase total DAT but a reduction surface DAT, which could be exacerbated by neuronal activity. revealed loss is specifically impaired 5’-phosphatase activity hyperactive downstream PI(4,5)P2-PKCbeta pathway. Thus, our findings provided important mechanistic insight for Synj1-regulated trafficking integral dysfunctional DA signaling early parkinsonism.

Language: Английский

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Haploinsufficiency of the Parkinson’s disease gene synaptojanin1 is associated with abnormal responses to psychomotor stimulants and mesolimbic dopamine signaling

Frontiers in Behavioral Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: July 10, 2024

The synaptojanin-1 ( SYNJ1 ) gene is known to be important for dopamine-related disorders. Recent evidence has demonstrated that Synj1 deficient mice +/− have impairments in dopaminergic synaptic vesicular recycling. However, less about how deficits affect the mesolimbic system, reward processing, and motivated behavior. To examine role of behavior, we subjected male female +/+ a battery behavioral tests evaluating hedonic responses, effortful responding, responses psychomotor stimulants. We observed exhibit few differences processing with normal responding sucrose. but not an attenuated conditioned place preference cocaine could attributed spatial memory. further understand dopamine signaling underlying response these mutant mice, recorded nucleus accumbens took longer reach peak release following experimenter-administered cocaine. also showed slower decay appear linked cocaine-induced DAT responses. These findings demonstrate deficiencies result abnormal DA which previously been demonstrated. Our work highlights need develop targeted therapeutics capable restoring function, may effective reversing pathologies associated mutations.

Language: Английский

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Parkinson’s disease gene, Synaptojanin1, dysregulates the surface maintenance of the dopamine transporter

npj Parkinson s Disease, Journal Year: 2024, Volume and Issue: 10(1)

Published: Aug. 8, 2024

Missense mutations of PARK20/SYNJ1 (synaptojanin1/Synj1) were found in complex forms familial Parkinsonism. However, the Synj1-regulated molecular and cellular changes associated with dopaminergic dysfunction remain unknown. We now report a fast depletion evoked dopamine impaired maintenance axonal transporter (DAT) Synj1 haploinsufficient (Synj1+/−) neurons. While has been traditionally known to facilitate endocytosis synaptic vesicles, we provide vitro vivo evidence demonstrating that haploinsufficiency results an increase total DAT but reduction surface DAT. Synj1+/− neurons exhibit maladaptive trafficking, which could contribute altered DA release. showed loss is 5'-phosphatase activity hyperactive PI(4,5)P2–PKCβ pathway downstream deficiency. Thus, our findings provided important mechanistic insight for trafficking integral dysfunctional signaling, might be relevant early

Language: Английский

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Protocol for live neuron imaging analysis of basal surface fraction and dynamic availability of the dopamine transporter using DAT-pHluorin

STAR Protocols, Journal Year: 2024, Volume and Issue: 5(4), P. 103358 - 103358

Published: Oct. 4, 2024

Language: Английский

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