Parkin targets NOD2 to regulate astrocyte endoplasmic reticulum stress and inflammation.
Loss of substantia nigra dopaminergic neurons results in Parkinson disease (PD). Degenerative PD usually presents in the seventh decade whereas genetic disorders, including mutations in PARK2, predispose to early onset PD. PARK2 encodes the parkin E3 ubiquitin ligase which confers pleotropic effects on mitochondrial and cellular fidelity and as a ... mediator of endoplasmic reticulum (ER) stress signaling. Although the majority of studies investigating ameliorative effects of parkin focus on dopaminergic neurons we found that astrocytes are enriched with parkin. Furthermore, astrocytes deficient in parkin display stress-induced elevation of nucleotide-oligomerization domain receptor 2 (NOD2), a cytosolic receptor integrating ER stress and inflammation. Given the neurotropic and immunomodulatory role of astrocytes we reasoned that parkin may regulate astrocyte ER stress and inflammation to control neuronal homeostasis. We show that, in response to ER stress, parkin knockdown astrocytes exhibit exaggerated ER stress, JNK activation and cytokine release, and reduced neurotropic factor expression. In coculture studied we demonstrate that dopaminergic SHSY5Y cells and primary neurons with the presence of parkin depleted astrocytes are more susceptible to ER stress and inflammation-induced apoptosis than wildtype astrocytes. Parkin interacted with, ubiquitylated and diminished NOD2 levels. Additionally, the genetic induction of parkin ameliorated inflammation in NOD2 expressing cells and knockdown of NOD2 in astrocytes suppressed inflammatory defects in parkin deficient astrocytes and concurrently blunted neuronal apoptosis. Collectively these data identify a role for parkin in modulating NOD2 as a regulatory node in astrocytic control of neuronal homeostasis.
Mesh Terms:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Astrocytes, Cells, Cultured, Cytokines, Endoplasmic Reticulum Stress, Gene Expression Regulation, HEK293 Cells, Humans, Inflammation, L-Lactate Dehydrogenase, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Growth Factors, Nod2 Signaling Adaptor Protein, Oncogene Protein p55(v-myc), Oxidopamine, Transcription Factor CHOP, Ubiquitin-Protein Ligases
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Astrocytes, Cells, Cultured, Cytokines, Endoplasmic Reticulum Stress, Gene Expression Regulation, HEK293 Cells, Humans, Inflammation, L-Lactate Dehydrogenase, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Growth Factors, Nod2 Signaling Adaptor Protein, Oncogene Protein p55(v-myc), Oxidopamine, Transcription Factor CHOP, Ubiquitin-Protein Ligases
Glia
Date: Dec. 01, 2017
PubMed ID: 30378174
View in: Pubmed Google Scholar
Download Curated Data For This Publication
218506
Switch View:
- Interactions 1