Astroglial DJ-1 over-expression up-regulates proteins involved in redox regulation and is neuroprotective in vivo

Abstract

DJ-1, a Parkinson's disease-associated protein, is strongly up-regulated in reactive astrocytes in Parkinson's disease. This is proposed to represent a neuronal protective response, although the mechanism has not yet been identified. We have generated a transgenic zebrafish line with increased astroglial DJ-1 expression driven by regulatory elements from the zebrafish GFAP gene. Larvae from this transgenic line are protected from oxidative stress-induced injuries as caused by MPP+, a mitochondrial complex I inhibitor shown to induce dopaminergic cells death. In a global label-free proteomics analysis of wild type and transgenic larvae exposed to MPP+, 3418 proteins were identified, in which 366 proteins were differentially regulated. In particular, we identified enzymes belonging to primary metabolism to be among proteins affected by MPP+ in wild type animals, but not affected in the transgenic line. Moreover, by performing protein profiling on isolated astrocytes we showed that an increase in astrocytic DJ-1 expression up-regulated a large group of proteins associated with redox regulation, inflammation and mitochondrial respiration. The majority of these proteins have also been shown to be regulated by Nrf2. These findings provide a mechanistic insight into the protective role of astroglial up-regulation of DJ-1 and show that our transgenic zebrafish line with astrocytic DJ-1 over-expression can serve as a useful animal model to understand astrocyte-regulated neuroprotection associated with oxidative stress-related neurodegenerative disease.

Glial Contribution to Excitatory and Inhibitory Synapse Loss in Neurodegeneration

“…DJ-1, encoded by PARK7 gene, is a ubiquitously-expressed multifunctional protein which regulates anti-oxidant and anti-apoptotic gene expression (Canet-Avilés et al, 2004). DJ-1 knockdown in astrocytes was shown to impair astrocyte-mediated neuroprotection in primary neurons (Mullett and Hinkle, 2009; Kim et al, 2016), whereas astrocytic over-expression of DJ-1 prevented oxidative stress and mitochondrial dysfunction, leading to enhanced neuronal survival in vitro and in vivo (De Miranda et al, 2018; Frøyset et al, 2018). On the other hand, DJ-1 has been also shown to modulate microglial function, with its deficiency impairing autophagy, reducing α-syn phagocytosis and inducing a constitutive pro-inflammatory activation (Meiser et al, 2016; Nash et al, 2017).…”

α-Synuclein disrupts the anti-inflammatory role of Drd2 via interfering β-arrestin2-TAB1 interaction in astrocytes

“…They are the main causes of synaptic dysfunction and neuronal death, leading to a self-amplifying cycle of inflammation, and eventually accelerate the process of PD [ 16 ]. Besides reactive microglia along with Lewy bodies that found in the substantia nigra of PD patients, it is now increasingly appreciated that astrocytes also function in initiating and perpetuating inflammatory process associated with PD [ 17 , 18 ]. Thus, controlling astroglial-mediated neuroinflammation may prove to be a promising therapeutic strategy for PD.…”

Protein Promiscuity in H2O2Signaling

“…Despite not being enzymes of the cellular antioxidant system, GAPDH, DJ-1, TG2, and CypA are all differentially expressed in response to oxidative stress (78), and there is some evidence to support crossregulatory influences in transcription of these moonlighting proteins in response to stress conditions. In human neuroblastoma cell lines expressing a mutant overoxidant mimic of DJ-1 (C106DD), expression of TG2 was downregulated and ASK1 upregulated relative to cells containing wild-type DJ-1 (285), and astroglial DJ-1 overexpression has been shown to relate to upregulation of CypA (102). The ''polygamous'' influence of these moonlighting proteins cannot be understated and a further spectrum of complexity can arise from functional interactions between the moonlighting proteins themselves, such as TG2 transamidating GAPDH (152) and DJ-1 deglycating the glycated form of GAPDH (304).…”

“…Keap1 is a cysteine-rich (27 cysteines in the human isoform), 70-kDa protein that, under basal conditions, binds to Nrf2 and facilitates the association of the adapter component of the cullin 3 (Cul3)-based ubiquitin E3 ligase complex, leading to ubiquitination and proteasomal Nrf2 degradation (81). Astroglial overexpression of DJ-1 results in upregulation of the antioxidant enzymes, PrxII, Trx, and SOD1, although this could purely derive from the positive regulation of Nrf2 by DJ-1 (102).…”