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The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson's models.

ABSTRACT: Neurodegenerative diseases represent an increasing burden in our aging society, yet the underlying metabolic factors influencing onset and progression remain poorly defined. The relationship between impaired IGF-1/insulin-like signaling (IIS) and lifespan extension represents an opportunity to investigate the interface of metabolism with age-associated neurodegeneration. Using data sets of established DAF-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens in worms to select for daf-2-associated genetic modifiers of ?-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson's disease. An outcome of this strategy was the identification of GPI-1/GPI, an enzyme in glucose metabolism, as a daf-2-regulated modifier that acts independent of the downstream cytoprotective transcription factor DAF-16/FOXO to modulate neuroprotection. Subsequent mechanistic analyses using Drosophila and mouse primary neuron cultures further validated the conserved nature of GPI neuroprotection from ?-synuclein proteotoxicity. Collectively, these results support glucose metabolism as a conserved functional node at the intersection of proteostasis and neurodegeneration.

SUBMITTER: Knight AL

PROVIDER: S-EPMC4097176 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson's models.

Knight Adam L AL Yan Xiaohui X Hamamichi Shusei S Ajjuri Rami R RR Mazzulli Joseph R JR Zhang Mike W MW Daigle J Gavin JG Zhang Siyuan S Borom Akeem R AR Roberts Lindsay R LR Lee S Kyle SK DeLeon Susan M SM Viollet-Djelassi Coralie C Krainc Dimitri D O'Donnell Janis M JM Caldwell Kim A KA Caldwell Guy A GA

Cell metabolism 20140529 1

Neurodegenerative diseases represent an increasing burden in our aging society, yet the underlying metabolic factors influencing onset and progression remain poorly defined. The relationship between impaired IGF-1/insulin-like signaling (IIS) and lifespan extension represents an opportunity to investigate the interface of metabolism with age-associated neurodegeneration. Using data sets of established DAF-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens ...[more]

PMID: 24882066

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Project description:Chronic microglial activation has been linked to the progressive degeneration of the nigrostriatal dopaminergic neurons evidenced in Parkinson's disease (PD) pathogenesis. The exact etiology of PD remains poorly understood. Although both oxidative stress and neuroinflammation are identified as co-contributors in PD pathogenesis, signaling mechanisms underlying neurodegenerative processes have yet to be defined. Indeed, we recently identified that protein kinase C delta (PKC?) activation is critical for induction of dopaminergic neuronal loss in response to neurotoxic stressors. However, it remains to be defined whether PKC? activation contributes to immune signaling events driving microglial neurotoxicity. In the present study, we systematically investigated whether PKC? contributes to the heightened microglial activation response following exposure to major proinflammatory stressors, including ?-synuclein, tumor necrosis factor ? (TNF?), and lipopolysaccharide (LPS). We report that exposure to the aforementioned inflammatory stressors dramatically upregulated PKC? with a concomitant increase in its kinase activity and nuclear translocation in both BV-2 microglial cells and primary microglia. Importantly, we also observed a marked upregulation of PKC? in the microglia of the ventral midbrain region of PD patients when compared to age-matched controls, suggesting a role for microglial PKC? in neurodegenerative processes. Further, shRNA-mediated knockdown and genetic ablation of PKC? in primary microglia blunted the microglial proinflammatory response elicited by the inflammogens, including ROS generation, nitric oxide production, and proinflammatory cytokine and chemokine release. Importantly, we found that PKC? activated NF?B, a key mediator of inflammatory signaling events, after challenge with inflammatory stressors, and that transactivation of NF?B led to translocation of the p65 subunit to the nucleus, I?B? degradation and phosphorylation of p65 at Ser536. Furthermore, both genetic ablation and siRNA-mediated knockdown of PKC? attenuated NF?B activation, suggesting that PKC? regulates NF?B activation subsequent to microglial exposure to inflammatory stimuli. To further investigate the pivotal role of PKC? in microglial activation in vivo, we utilized pre-clinical models of PD. We found that PKC? deficiency attenuated the proinflammatory response in the mouse substantia nigra, reduced locomotor deficits and recovered mice from sickness behavior in an LPS-induced neuroinflammation model of PD. Likewise, we found that PKC? knockout mice treated with MPTP displayed a dampened microglial inflammatory response. Moreover, PKC? knockout mice exhibited reduced susceptibility to the neurotoxin-induced dopaminergic neurodegeneration and associated motor impairments. Taken together, our studies propose a pivotal role for PKC? in PD pathology, whereby sustained PKC? activation drives sustained microglial inflammatory responses and concomitant dopaminergic neurotoxicity consequently leading to neurobehavioral deficits. We conclude that inhibiting PKC? activation may represent a novel therapeutic strategy in PD treatment.

Dataset Information

The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson's models.

Publications

The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson's models.

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