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Fig. 6 | Molecular Neurodegeneration

Fig. 6

From: Lentiviral vector-mediated overexpression of mutant ataxin-7 recapitulates SCA7 pathology and promotes accumulation of the FUS/TLS and MBNL1 RNA-binding proteins

Fig. 6

Phosphorylated TDP-43 and FUS/TLS accumulate in the cerebellum of the LV-mouse model of SCA7. Laser confocal microscopy showing that murine TDP-43 (red) remains diffuse in a Purkinje cell transduced with WT ATXN7 (green) at 12 weeks post-injection (a). Murine TDP-43 (red) does not co-aggregate in MUT ATXN7-positive inclusions (green) at 12 weeks post-injection (b). Partial co-localization of MUT ATXN7 (green) and phosphorylated TDP-43 (red) (~12 %) was observed in GCL (d); nuclear WT ATXN7 (green) does not co-localize with phosphorylated TDP-43 (c) in PCs (n = 5). e Representative western-blot of cerebellar lysates shows a ~1.6-fold increased level of a 25-kDa band of phosphorylated-TDP-43 in mice injected with LV-MUT-ATXN7 compared to non-injected mice or mice injected with LV-WT-ATXN7 (n = 3). f and g Optical densitometry was normalized according to the amount of actin loaded in the corresponding lane. A partition ratio was calculated and expressed as optical densitometry (arbitrary units) relative to the sample with highest value for the normalization control set at 1. Values are expressed as mean ± standard error (SEM) of the mean. *p ≤ 0.05 (one-way ANOVA). All data are from 3 mice/group. hk Laser confocal microscopy showing co-aggregation of MUT ATXN7 (green) and FUS/TLS (red) in GCL in mice injected with LV-MUT-ATXN7 (69.6 ± 7.4 %), 12 weeks post-injection (I); in regions transduced with WT ATXN7 co-localization of WT ATXN7 with diffuse FUS/TLS in GCL, but no aggregation is observed (H). In the GCL transduced with MUT ATXN7, FUS/TLS is trapped into the ATXN7 inclusion and diffuse nuclear FUS/TLS fluorescence was decreased (see arrow) (K); in the contrary, in the non-transduced GCL (J) or in PCs transduced (H) with WT ATXN7 (green), FUS/TSL immunoreactivity was diffuse as well as WT ATXN7 in PCs (H). l Representative western-blot of cerebellar lysates shows reduced FUS/TLS levels (~50 %) (L) in mice injected with LV-MUT-ATXN7 compared to non-injected mice or mice injected with LV-WT-ATXN7 (n = 3). m Optical densitometry was normalized as indicated in panel F and G. Values are expressed as mean ± standard error (SEM) of the mean. *p ≤ 0.05 (Student’s T test). All data are from 3 mice/group. Bars: A–D: 20 μm; H and I: 10 μm; J and K: 3 μm

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