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Sonic Hedgehog repression underlies gigaxonin mutation–induced motor deficits in giant axonal neuropathy
Yoan Arribat, … , Mireille Rossel, Pascale Bomont
Yoan Arribat, … , Mireille Rossel, Pascale Bomont
Published September 10, 2019
Citation Information: J Clin Invest. 2019;129(12):5312-5326. https://doi.org/10.1172/JCI129788.
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Research Article Neuroscience

Sonic Hedgehog repression underlies gigaxonin mutation–induced motor deficits in giant axonal neuropathy

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Abstract

Growing evidence shows that alterations occurring at early developmental stages contribute to symptoms manifested in adulthood in the setting of neurodegenerative diseases. Here, we studied the molecular mechanisms causing giant axonal neuropathy (GAN), a severe neurodegenerative disease due to loss-of-function of the gigaxonin–E3 ligase. We showed that gigaxonin governs Sonic Hedgehog (Shh) induction, the developmental pathway patterning the dorso-ventral axis of the neural tube and muscles, by controlling the degradation of the Shh-bound Patched receptor. Similar to Shh inhibition, repression of gigaxonin in zebrafish impaired motor neuron specification and somitogenesis and abolished neuromuscular junction formation and locomotion. Shh signaling was impaired in gigaxonin-null zebrafish and was corrected by both pharmacological activation of the Shh pathway and human gigaxonin, pointing to an evolutionary-conserved mechanism regulating Shh signaling. Gigaxonin-dependent inhibition of Shh activation was also demonstrated in primary fibroblasts from patients with GAN and in a Shh activity reporter line depleted in gigaxonin. Our findings establish gigaxonin as a key E3 ligase that positively controls the initiation of Shh transduction, and reveal the causal role of Shh dysfunction in motor deficits, thus highlighting the developmental origin of GAN.

Authors

Yoan Arribat, Karolina S. Mysiak, Léa Lescouzères, Alexia Boizot, Maxime Ruiz, Mireille Rossel, Pascale Bomont

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Figure 6

Decreased responsiveness of primary fibroblasts from patients with GAN to the activation of the Shh pathway.

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Decreased responsiveness of primary fibroblasts from patients with GAN t...
(A) Shh-CM treatment for 4 hours causes translocation of Smo into the cilium (arl13b) in control but this is greatly decreased in patient primary fibroblasts, bearing distinct mutations in the GAN gene: GANΔex10-11 and GANA49E. Quantification of the proportion of Smo-positive cilia in control and GAN fibroblasts, with or without Shh treatment, is shown at the bottom. Statistics: proportions of experimental groups were compared with the χ2 test, data represent mean ± SEM; n = 419 (GANWT), n = 410 (GANWT+Shh), n = 179 (GANΔex10-11), n = 135 (GANΔex10-11+Shh), n = 295 (GANA49E), n = 347 (GANA49E+Shh) from 5 independent experiments; **P < 0.01, ****P < 0.0001 correspond to the comparison between patient and control cells in the presence of Shh (pairwise comparisons of patient with control cells are not statistically significant in the absence of Shh). (B) Shh-CM treatment for 24 hours increases the length of primary cilia in control but not in GANΔex10-11 and GANA49E patient primary fibroblasts. Quantification of the ciliary length in human fibroblasts, showing a significant increase upon Shh-CM stimulation in control but not in mutant cells, is shown at the bottom. Statistics: with normality of the distribution of the data, a 1-way ANOVA test (with Bonferroni’s post hoc test) was used, mean ± SEM; n = 24 (GANWT), n = 26 (GANWT+Shh), n = 19 (GANΔex10-11), n = 28 (GANΔex10-11+Shh), n = 22 (GANA49E), n = 23 (GANA49E+Shh); NS, not statistically significant; **P < 0.01. Scale bars: 10 μm. Insets: Original magnification ×2.
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