Extended Data Fig. 7: Digesting cytosolic dsDNA in neurons by DNase cures LSDs.
From: Innate immune sensing of lysosomal dysfunction drives multiple lysosomal storage disorders
(a, b) Immunohistochemistry staining of NeuN (a) and its quantification (b) indicated that mTrex1 therapy prevented the neuronal death of 12-week-old mice with Hexb deletion. Scale bars, 1 mm (left), 100 μm (right). n = 20 slices pooled from 4 mice in each group. (c, d) Immunofluorescence imaging displayed that the number of surviving Purkinje cells was significantly increased in Npc1-/- mice with AAV-mTrex1-3x Flag administration, compared to AAV-mCherry administration (c). n = 20 slices pooled from 4 mice in WT + AAV-mCherry and WT + AAV-mTrex1 groups; n = 25 slices pooled from 5 mice in Npc1-/- + AAV-mCherry and Npc1-/- + AAV-mTrex1 groups (d). Scale bars, 100 μm. (e, f) mTrex1 therapy partially rescued symptoms of Niemann-Pick disease, including impairment of motor coordination and balance (e) and hindlimb clasping (f). n = 6 mice in WT + AAV-mCherry and WT + AAV-mTrex1 groups, and n = 5 mice in Npc1-/- + AAV-mCherry and Npc1-/- + AAV-mTrex1 groups. (g) Diagram indicating the experiment schedule of AAV administration, DRGs, and the analyses of footpads skin nerve fibres in WT and Gla-/- mice. (h, i) Immunofluorescence imaging revealed a diminished STING signalling in DRG neurons of Gla-/- mice in response to Trex1 therapy (h), as quantified by relative STING signal strength in individual mCherry+ or mTrex1-3xFlag+ DRG neurons in 6-month-old WT and Gla/- mice (i, n = 40 neurons). Scale bars, 20 μm. (j, k) Immunofluorescence imaging showed that mTrex1 therapy partially rescued the reduction in the number of small fibres from Gla-/- mice footpads (j) and quantified (k), n = 4 mice in WT + AAV-mCherry group, n = 5 mice in other groups. Scale bars, 100 μm. Error bars in graphs b-k represent mean ± SEM and P values were calculated by one-way ANOVA with Bonferroni correction.
