Boosting spastin microtubule-severing activity through TTLL-mediated tubulin polyglutamylation: a novel therapeutic strategy in SPG4-linked Hereditary Spastic Paraplegia.
Coralie Fassier & Maria Magiera
Mutations in the SPG4 gene are responsible for the most common form of autosomal dominant Hereditary Spastic Paraplegia, a neurological disorder characterized by the degeneration of axonal tracts controlling voluntary movements. The SPG4 gene encodes spastin, a protein essential for the remodelling of one of the main components of our cell skeleton, the microtubules. Microtubule remodelling underlies many cellular processes essential for neuronal homeostasis and survival. In order to circumvent the dysfunction of the cellular processes associated with spastin loss of function, our project aims at deciphering the mechanisms that regulate spastin activity. In this context, studies have shown that enzymes called glutamylases deposit specific marks on the microtubule surface which establish a code that regulate the activity of several proteins involved in microtubule remodelling. Thus, using a combination of experimental approaches ranging from in vitro systems to mouse and zebrafish animal models, our project aims to : (i) to identify the glutamylases that specifically stimulate spastin activity and (ii) to test whether modulation of their activities attenuates or prevents axonal degeneration associated with a lack of spastin, which could represent a new therapeutic avenue in Hereditary Spastic Paraplegia.