Spastin-driven microtubule remodelling: From neurodevelopmental defects to neurodegeneration – SpasTract

Nervous system disorders have long been dichotomized between early-onset neurodevelopmental traits and late-onset degenerative phenotypes. However, recent studies unveiled strong molecular and causal links between neurodevelopmental and neurodegenerative conditions, thereby challenging this classification. Notably, microtubule (MT)-related proteins gradually emerged as central players connecting neurodevelopmental defects to neurodegeneration. This highlights the need to decipher the role of cytoskeleton-regulatory proteins incriminated in neurodegenerative diseases during neuronal development to gain new perspectives on the aetiology and treatment of these disorders. Heterozygous loss of function mutations in the SPG4 gene encoding the MT-severing protein spastin cause the major form of Hereditary Spastic Paraplegia (HSP). This neurological disorder is characterized by the degeneration of corticospinal tracts (CST) and no curable treatment is available so far. A relevant strategy to prevent CST degeneration caused by spastin haploinsufficiency would be to boost its activity upon the critical threshold early in the disease time course. In this context, we uncovered spastin as a downstream effector of a key guidance pathway in CST development. Our project will use an original combination of biological systems (from in vitro-cell free systems to spastin KO mice) and advanced microscopy (multi-modal MRI, lightsheet, STED and TIRF) to (i) conduct the first dissection of spastin function in CST development from molecule to circuits. We will then assess the ability of key effectors of this pathway (ii) to promote spastin activity in developing neurons and (iii) rescue the degenerative process when manipulated in SPG4 cellular (including patient iPSC-derived neurons) and animal models. Our project will shed new lights on the aetiology of HSP and identify tractable therapeutic targets to overcome spastin haploinsufficiency and prevent/delay axonal degeneration in SPG4-HSP.