Rôle de la spastin dans le developpement des circuits moteurs et leur dégénérescence dans les paraplégies spastiques héréditaires

Abstract : Mutations in SPG4, encoding spastin cause the major form of Hereditary Spastic Paraplegias (HSP), a paralytic disorder characterised by the degeneration of the corticospinal tracts. Spastin and its close homologue p60-katanin are microtubule-severing enzymes (MSE) required for spinal motor neuron (SMN) axon extension during zebrafish development. However, their roles in SMN axon navigation which also rely on microtubules (MTs) remain elusive. My PhD work aimed at refining the functional specificity and redundancy of these MSE during motor circuit wiring and clarifying the physiopathology of SPG4-linked HSP. I have first contributed to show that p60-Katanin controls SMN axon targeting and larval locomotion in a dose-dependent manner. We also demonstrated that Spastin and p60-Katanin play differential roles in SMN navigation and identified TTLL6-mediated MT polyglutamylation as a key event in regulating p60-Katanin activity in this process. Concomitantly, I have conducted a functional analysis of spastin main isoforms (resulting from alternative translation, M1 and M61) during zebrafish development, which reveals their critical and specific involvement in two distinct signalling pathways that are both essential for motor circuit wiring and locomotor behaviours. This study has provided compelling evidences for a concerted role for M1 and other HSP proteins in the down-regulation of the BMP pathway and reveals a specific role for M87 as a downstream effector of Neuropilin-1 signalling. Altogether, our study emphasizes defective BMP signalling as a key pathogenic mechanism in HSP, and shows that dysregulation of the Neuropilin-1 pathway may equally contribute to SPG4-linked HSP.
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Nicolas Jardin. Rôle de la spastin dans le developpement des circuits moteurs et leur dégénérescence dans les paraplégies spastiques héréditaires. Neurosciences [q-bio.NC]. Université Pierre et Marie Curie - Paris VI, 2016. Français. ⟨NNT : 2016PA066601⟩. ⟨tel-01885505v2⟩

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