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. 2023 Jan 16;12:e82555. doi: 10.7554/eLife.82555

Figure 3. Ambroxol, Azoramide, Desipramine, and Genistein alleviate neurodegenerative phenotypes in INAD flies and patient-derived NPCs.

(A) Bang-sensitivity was used as a primary readout to select drugs that suppress neurodegeneration. Bang-sensitivity of control or INAD flies fed with the indicated drugs. Error bars represent SEM (n=3; 20 flies per assay). Redline highlights the time required for INAD flies to recover from bang-induced paralysis. Red ‘*‘ indicates drugs that significantly suppress bang-sensitivity. Black ‘*‘ indicates drugs that significantly promote bang-sensitivity (the p values were calculated between iPLA2-VIA∆174 and the indicated treatment). (B) Using INAD patient-derived NPCs to select drugs that suppress LAMP2 accumulation. PLA2G6 antibody was used to detect the endogenous PLA2G6 in the indicated cellular lysates. The intensity of the LAMP2/Actin is quantified at (C) (n=3). (D) Drugs that suppress LAMP2 accumulation also restore ATP levels. The relative amounts of ATP are measured in the indicated NPC lines with or without the treatment of the selected drugs (n=3). Error bars represent SEM; *p<0.05; **p<0.01; ***p<0.001; NS, not significant (the p values were calculated between the untreated patient NPCs (29-1) and the indicated treatment). References in Figure 3A: (Aflaki et al., 2016; Agostini et al., 2021; Alfonso et al., 2005; Desai et al., 2002; Fu et al., 2015; Hernandez et al., 2019; Hung et al., 2012; Hwang et al., 2019; Ke et al., 2020; Khanna et al., 2010; Liu et al., 2008; Magalhaes et al., 2018; Mauthe et al., 2018; Mistry et al., 2018; Moskot et al., 2014; Olanow et al., 2006; Rosen and Liao, 2003; Scott et al., 2016; Shen et al., 2012; Wang et al., 2021; Yang and Tohda, 2018; Zhu et al., 2019). INAD, infantile neuroaxonal dystrophy; NPC, neural progenitor cell.

Figure 3—source data 1. Ambroxol, Azoramide, Desipramine, or Genistein reduce LAMP2 levels in patient derived NPCs.
Figure 3—source data 2. Selected drugs tested in an INAD fly model.
Figure 3—source data 3. Raw gel images for Figure 3.

Figure 3.

Figure 3—figure supplement 1. Ambroxol, Azoramide, Desipramine, or Genistein suppress ERG defects and the loss of photoreceptor in INAD flies.

Figure 3—figure supplement 1.

(A) The ERG trace of the indicated genotypes and treatments. iPLA2-VIA∆174: the INAD flies; GR; iPLA2-VIA∆174: genomic rescued INAD flies (control) (Lin et al., 2018). (B) Quantifications of the LCRP amplitudes. (C) Quantifications of the on-transient amplitudes. (D) Ambroxol, Azoramide, Desipramine or Genistein reduce the loss of photoreceptor phenotype in INAD flies. Toluidine blue staining of the ommatidia of the flies with the indicated genotypes and treatment. Arrows indicate vacuoles. The number of photoreceptor per ommatidia is quantified in (E) (n=10). Scale bar=10 µm. Representative images are shown in this figure. Error bars represent SEM; ***p<0.001 (the p values were calculated between the untreated (No Drug) and the indicated column). ERG, electroretinogram; INAD, infantile neuroaxonal dystrophy; LCRP, light coincident receptor potential.