Fig. 8: Schematic drawing of the molecular mechanisms by which ULK1.DN attenuates axonal degeneration. | Cell Death & Differentiation

Fig. 8: Schematic drawing of the molecular mechanisms by which ULK1.DN attenuates axonal degeneration.

From: Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing

Fig. 8

a We have previously demonstrated the upregulation of ULK1 and autophagy during axonal degeneration after axonal lesion [12]. b In this study, ULK1.DN-mediated inhibition of ULK1 function significantly protects axons from degenerating in different models of lesion-induced axonal degeneration. Mechanistically, ULK1.DN decreases autophagy as demonstrated by altered levels of LC3 and p62. Autophagy inhibition attenuated axonal degeneration in our previous studies [8, 11] and is thus one of the mechanisms by which ULK1.DN exerts neuroprotective effects. Furthermore, ULK1.DN enhances translation through increased mTOR and S6 signaling. Increased translation represents a second mediator of the degeneration-attenuating effect of ULK1.DN, as dysregulated translation is implicated in axonal degenerative cascades [37, 38, 40, 59]. In addition, we demonstrate that ULK1.DN modulates the differential splicing of Kif1b, which plays a role in axonal transport and has previously been shown to be involved in axonal degeneration [52, 62, 63]. Similarly, Ddit3 is differentially spliced by ULK1.DN, which mediates ER stress and has been implicated in models of neurodegeneration [51, 66,67,68]. Differential splicing of these genes is therefore another mechanism by which ULK1.DN mediates the attenuation of axonal degeneration.

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