Accumulation of aggregated -synuclein can disrupt astrocyte function in general and, more importantly, can contribute to neurodegeneration in -synucleinopathies through various pathways. disease and propose a model of neuroglial connectome altered by -synuclein proteostasis that might be amenable to immune based therapies. and are expressed from mature astrocytes and unsurprisingly, most of these have been linked to neuroinflammatory response in preclinical models [21]. Therefore, it is possible that aside from disrupting neuronal function, these Syn variants also compromise astrocyte homeostasis. Some of these gene variants do not necessarily cause Syn pathology in all patients; however, by regulating mitophagy or redox function, these genes may cause generalized proteostasis imbalance or dysfunctional autophagic response in astrocytes leading to clinical symptoms reminiscent of Parkinsonism [21]. A common BGJ398 (NVP-BGJ398) BGJ398 (NVP-BGJ398) major cellular pathways affected by these genes is usually induction of oxidative stress causing widespread damage to cellular lipids, proteins, and DNA [41, 96, 114]. Indeed, accumulation of reactive oxygen species (ROS) can induce formation of TNTs [182], which has been shown by numerous groups to be conduits for Syn propagation between astrocytes and neurons [1, 132, 146]. A homeostatic response of astrocytes to mitigate ROS is usually by a redox-sensitive decrease in KEAP1 mediated degradation of a transcriptional regulator, Nrf2. This induces expression of anti-oxidant response elements (ARE) leading to expression of detoxification and antioxidant enzymes such as glutathione, metallothioneins, NAD(P)H Quinone Dehydrogenase 1 (NQO1) and heme oxygenase. Several preclinical studies have shown a protective effect of Nrf2 on -synucleinopathy [36, 57, 69, 72, 90, 171]. Interestingly, astrocytic Nrf2 overexpression rescues the phenotype and extends life span of human [A53T] Syn transgenic mice [57]. This has spurred multiple studies screening the neuroprotective effects of Nrf2 activators as potential PD therapeutics [44, 56, 76]. Impairment of these protective functions of astrocytes by Syn accumulation may contribute to neuronal demise, and restoration of them could represent avenues for therapeutic development (Physique 3). DJ-1 (encoded by and and may also impact astrocyte function and alter disease etiology through altering redox stress or other pathways (Physique 3). Whether mining such genetic and risk factor data can enable stratification of patients for personalizing treatment options, based on their unique clinical presentation, should be examined in future therapeutic studies. Current strategies of harnessing immunoproteostasis by either using small molecule drugs or astrocyte-derived neurotrophic molecules or astrocyte transplantation in combination with immunotherapy remain intriguing and will have to be tested in multiple models of -synucleinopathies (Physique 3). Overall, bilateral interactions or non-cell autonomous interactions between astrocytes and neurons or other glia in specific regions of the brain may provide us insights into neuronal dysfunction and death (Physique 3). Deeper knowledge of astrocyte biology and its functional alterations will be necessary before we can successfully embark on such disease modifying therapies in -synucleinopathies. BOX 1: CRITICAL OUTSTANDING QUESTIONS What is the source of astrocytic -synuclein? Does a bilateral communication between neurons and astrocytes lead to exacerbated disease? What is the mechanism of bilateral transmission of Syn C direct physical contact or passive uptake? How do the astrocyte-resident PD risk genes lead to Mouse monoclonal antibody to TAB1. The protein encoded by this gene was identified as a regulator of the MAP kinase kinase kinaseMAP3K7/TAK1, which is known to mediate various intracellular signaling pathways, such asthose induced by TGF beta, interleukin 1, and WNT-1. This protein interacts and thus activatesTAK1 kinase. It has been shown that the C-terminal portion of this protein is sufficient for bindingand activation of TAK1, while a portion of the N-terminus acts as a dominant-negative inhibitor ofTGF beta, suggesting that this protein may function as a mediator between TGF beta receptorsand TAK1. This protein can also interact with and activate the mitogen-activated protein kinase14 (MAPK14/p38alpha), and thus represents an alternative activation pathway, in addition to theMAPKK pathways, which contributes to the biological responses of MAPK14 to various stimuli.Alternatively spliced transcript variants encoding distinct isoforms have been reported200587 TAB1(N-terminus) Mouse mAbTel+86- proteostasis failure in glia C through direct or non cell autonomous pathways? Does astrocytic dysfunction precede Syn proteinopathy or is the dysfunction a result of neuronal Syn proteinopathy? Does astrocytic metabolism of internalized Syn result in harmful by-products that contribute to disease pathogenesis? Is usually restoring astrocytic function sufficient to rebalance proteostasis as a monotherapy? Acknowledgement This work was supported by NIH grant NS099738 (PC) and NS089622 (BIG). We acknowledge the University or college of Florida Neuromedicine Brain Bank for usage of human tissue examples. Abbreviations Syn-synucleinAKTAK thymomaAREAnti-oxidant response elementCNSCentral Anxious SystemCDNFCerebral dopamine neurotrophic factorCSFCerebrospinal fluidDAMPDamage linked molecular patternDLBDementia with Lewy BodiesEMElectron MicroscopeFAFormic AcidFoxa1Forkhead BGJ398 (NVP-BGJ398) Container A1GABAGamma-Amino Butyric acidGDNFGlial cell line-derived neurotrophic factorGCIGlial cytoplasmic inclusionsGFAPGlial Fibrillary Acidic ProteinGLP1RGlucagon-like peptide-1 receptorGBAGlucosidase beta acidH&EHematoxylin & Eosin stainingHLA-DRHuman leukocyte antigen DR isotypeMHC-IIMajor histocompatibility complicated course IIMMPMatrix metalloproteinaseMANFMesencephalic astrocyte-derived neurotrophic factorHLA-DRHuman Leukocyte Antigen C DR isotypeiLBDIncidental Lewy body diseasesKeap1Kelch-like ech-associated proteins 1LRRK2Leucine-rich do it again kinase 2LBLewy bodiesLNLewy neuritesMSAMultiple Program AtrophyNQO1NAD(P)H Quinone Dehydrogenase 1NCINeuronal cytoplasmic inclusionsNRTNNeurturinNACNon-amyloid componentNrf2Nuclear aspect erythroid 2-like 2NFBNuclear aspect -light-chain-enhancer of turned on B cellsNurr1/NR4A2Nuclear receptor subfamily 4, group A,.