Nrf2 inducer and cncC overexpression attenuates neurodegeneration due to α-synuclein in Drosophila

Abstract

The study of the genes that are related to the pathogenesis of Parkinson's disease (PD) will improve our understanding of the mechanisms that underlie the development of PD. α-Synuclein is a major protein component of Lewy bodies, which are characteristic structures of PD pathology. Mutations in α-synuclein are closely related to the early onset of autosomal dominant PD. Transgenic flies with mutant α-synuclein (A53T) display neurodegenerative changes that include movement dysfunctions and a loss of dopaminergic neurons in the brain. In the present study, we measured reactive oxygen species (ROS) levels in α-synuclein transgenic flies by monitoring the fluorescence levels of redox-sensitive indicators based on GFP (roGFP) in flies co-expressing roGFP and mutant α-synuclein. We found that the ROS levels were significantly increased in the mutant α-synuclein flies. The elevations in ROS levels were also proportionate to the behavioral disorders and the losses of dopaminergic neurons. We also found that CDDO-Me inhibited the increases in ROS levels in the A53T flies and improved the neurodegenerative changes by activating the Nrf2/antioxidant response element signaling pathway. Selective expression of the Nrf2 homologous gene cncC in the dopaminergic neurons effectively protected against the neurodegenerative phenotype of the A53T α-synuclein flies, compared to the flies that expressed cncC in all neurons. These results indicate that the reductions in oxidative stress that are mediated by the activation of the antioxidant signaling pathway can effectively attenuate the neurotoxicity caused by mutations in α-synuclein.

Topovectorial mechanisms control the juxtamembrane proteolytic processing of Nrf1 to remove its N-terminal polypeptides during maturation of the CNC-bZIP factor

“…However, it should be noted that such striking changes in their transactivation activity did not appear to be attributed to differences in total levels of the above-examined fusion proteins ( Figure 2B, cf. lanes [1][2][3][4][5][6][7][8][9][10]. Overall, these data demonstrate that the core h-region (aa 11-22) of TM1-adjoining NHB1 peptide, and the whole NHB2 (aa 81-106) peptide, as well as the CRAC1/2-adjoining sequence between NHB1 and NHB2, are essential for negative stepwise regulation of AD1 by NTD.…”

“…Furthermore, putative ubiquitination of Nrf1 is not a prerequisite necessary for involvement of p97 in the client processing. Overall, the regulated juxtamembrane proteolysis (RJP) of Nrf1, though occurring in close proximity to the ER, is distinctive from the mechanism that regulates the intramembrane proteolytic (RIP) processing of ATF6 and SREBP1.transcription factor is enabled to bind its cognate gene promoters [7][8][9][10]. Of note, selective processing of Nrf1 (and its long TCF11) via various mechanisms yields multiple isoforms of between 140-kDa and 25-kDa, which exert different and even opposing biological activities.…”

“…transcription factor is enabled to bind its cognate gene promoters [7][8][9][10]. Of note, selective processing of Nrf1 (and its long TCF11) via various mechanisms yields multiple isoforms of between 140-kDa and 25-kDa, which exert different and even opposing biological activities.…”

The lysosomal membrane protein LAMP2A promotes autophagic flux and prevents SNCA-induced Parkinson disease-like symptoms in the Drosophila brain

“…Previous reports in Drosophila and mouse suggest that the neurotoxicity of SNCA could be partly caused by an increase in oxidative stress associated with the abnormal accumulation of this protein [52,[55][56][57][58]. This prompted us to analyze the levels of reactive oxygen species (ROS) in whole-mount Drosophila brains using dihydroethidium (DHE) dye fluorescence.…”

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“…This is mainly because they degenerate in an age-dependent manner and this degeneration manifests as deficiency in locomotor function (Botella et al 2009;Feany & Bender 2000;Park, Schulz & Lee 2007;Staveley 2014). The key elements of the original Drosophila model of Parkinson disease that utilizes the expression of a human α-synuclein transgene to induce the PD-like symptoms (Feany & Bender 2000); is its ability to recapitulate some features of human PD that include, age-dependent loss of DA neurons that manifest in age-dependent loss in locomotor function (Auluck et al 2002;Botella et al 2009;Buttner et al 2014;Feany & Bender 2000;Kong et al 2015;Staveley 2014;Wang et al 2015;Zhu et al 2016). The spatio-temporal UAS/GAL4 expression system (Brand & Perrimon 1993), and the availability of a plethora of promoters or enhancers of which TH-Gal4, elav-Gal4 and Ddc-Gal4 are employed to model PD in flies (Auluck et al 2002;Botella et al 2009;Buttner et al 2014;Feany & Bender 2000;Kong et al 2015;Staveley 2014;Wang et al 2015;Zhu et al 2016).…”