Subregional differences in astrocytes underlie selective neurodegeneration or protection in Parkinson's disease models in culture

Abstract

Parkinson's disease (PD) is characterized by the selective degeneration of dopamine (DA) neurons of the substantia nigra pars compacta (SN), while the neighboring ventral tegmental area (VTA) is relatively spared. The mechanisms underlying this selectivity are not fully understood. Here, we demonstrate a vital role for subregional astrocytes in the protection of VTA DA neurons. We found that elimination of astrocytes in vitro exposes a novel vulnerability of presumably protected VTA DA neurons to the PD mimetic toxin MPP+, as well as exacerbation of SN DA neuron vulnerability. Conversely, VTA astrocytes protected both VTA and SN DA neurons from MPP+ toxicity in a dose dependent manner, and this protection was mediated via a secreted molecule. RNAseq analysis of isolated VTA and SN astrocytes demonstrated a vast array of transcriptional differences between these two closely related populations demonstrating regional heterogeneity of midbrain astrocytes. We found that GDF15, a member of the TGFβ superfamily which is expressed 230‐fold higher in VTA astrocytes than SN, recapitulates neuroprotection of both rat midbrain and iPSC‐derived DA neurons, whereas its knockdown conversely diminished this effect. Neuroprotection was likely mediated through the GRFAL receptor expressed on DA neurons. Together; these results suggest that subregional differences in astrocytes underlie the selective degeneration or protection of DA neurons in PD.

Reactive Astrocytes as Therapeutic Targets for Brain Degenerative Diseases: Roles Played by Metabotropic Glutamate Receptors

“…Such differences are also noted when substantia nigra astrocytes are compared to those of the ventral tegmental area. In this case, recent studies of effects of astrocytes on local dopaminergic neurons suggest that growth and differentiation factor 15 (GDF15), a member of the transforming growth factor beta (TGF-β) superfamily, may be responsible for differences in survival and protection when dopaminergic neurons from the two brain regions are compared [23].…”

Glutaredoxin 1 Downregulation in the Substantia Nigra Leads to Dopaminergic Degeneration in Mice

“…This selectivity is reminiscent of human PD and the MPTP‐induced neurodegeneration in mouse and nonhuman primate models 48 and suggests that VTA dopaminergic neurons may be protected from Grx1 downregulation through cell‐intrinsic and/or extrinsic mechanisms. Several other factors that make VTA DA neurons relatively less vulnerable have also been reported 48‐50 . For example, DA neurons in the VTA are more protected against oxidative stress than nigral neurons because they are in an environment with more astrocytes expressing the antioxidant enzyme glutathione peroxidase 51 …”

Manganese exposure in juvenile C57BL/6 mice increases glial inflammatory responses in the substantia nigra following infection with H1N1 influenza virus

“…It is still unclear whether neuroinflammatory activation of glia increases susceptibility to neurodegeneration primarily through decreased release of neurotrophic factors or from excessive synthesis of neurotoxic inflammatory mediators [ 47 , 54 ]. Glial activation is regulated through multiple pathways including mitogen-activated protein kinases (MAPKs), activator protein-1 (AP-1), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), interferon regulatory factor families (IFN), as well as through the nuclear factor kappa B (NFκB) pathway.…”