Parkin targets NOD2 to regulate astrocyte endoplasmic reticulum stress and inflammation

Abstract

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.

Neuroglial transmitophagy and Parkinson's disease

“…PINK1 has a low basal expression which is undetectable with immunohistochemical methods, and its finding in spheroids suggests it accumulates in their mitochondria. Parkin normally exists in an inactive auto‐inhibited conformation which changes when its serine 65 is phosphorylated by the action of the autophosphorylated PINK1 (Chin & Li, 2016; Pickrell & Youle, 2015; Singh et al, 2018). The spheroids showed high parkin immunoreactivity, a fact also found for ubiquitin, a protein which links covalently to other proteins (ubiquitination) and works as a “kiss of death” signal for mitophagy (Chin & Li, 2016; de Rivero Vaccari et al, 2012; Rogov, Dotsch, Johansen, & Kirkin, 2014; C. Y. Wang, Deneen, & Tzeng, 2019).…”

Maackiain Ameliorates 6-Hydroxydopamine and SNCA Pathologies by Modulating the PINK1/Parkin Pathway in Models of Parkinson’s Disease in Caenorhabditis elegans and the SH-SY5Y Cell Line

“…In a previous report, MK exhibited inhibitory effects on LPS-induced nitric oxide production in RAW 264.7 macrophages [ 30 ] and inhibited 5-lipoxygenase and OVA-induced airway inflammation [ 67 ]. Moreover, Singh et al showed that parkin can target the nucleotide binding oligomerization domain containing 2 protein (NOD2) to regulate astrocyte endoplasmic reticulum stress and inflammation [ 68 ]. In our study, MK could increase parkin expression and may reverse astrocyte-associated inflammation.…”

The Role of Rare Coding Variants in Parkinson's Disease GWAS Loci

“…SH3GL2 is also responsible for recruitment of dynamin to clathrin-coated vesicles (20). Parkin interacts with NOD2 for regulation of stress and inflammation; Parkin knockdown in mouse dopaminergic neurons exhibited increased NOD2 expression and endoplasmic reticulum stress and cytokine release (21). NOD2 deficiency was protective against 6-OHDA-induced DA degeneration and neuronal death (22), suggesting that the identified NOD2 variants in our patients may be toxic gain of function.…”