Genetic determinism and functional and pharmacological evaluation of spinocerebellar degenerative disorders linked to lipid gene mutations. – LIGENAX

Hereditary spastic paraplegia (HSP) and cerebellar ataxias (CA) are rare diseases of the central nervous system often referred to as spinocerebellar degenerations because of the great clinical overlap that exist between these diseases. HSP is characterized by gradual spasticity and weakness of the lower limbs, and is usually caused by developmental failure or degeneration of motor axons in the corticospinal tract. CA are rare inherited progressive disorders in which the cerebellum slowly degenerates, often accompanied by degenerative changes in the brainstem and elsewhere. Recent studies, performed in particular by members of the LIGENAX project, have focused on an abnormal lipid metabolism as the novel pathological mechanism involved. Our proposal focuses on recently identified CYP7B1 (SPG5) (Goizet et al. 2009), CYP2U1 (SPG47) and ABHD12 (unpublished data) mutations, correlated to these neurological conditions. As gene data are only correlative, the only way to demonstrate causality is via function. We intend to screen a large population of patients for mutations in these disease-associated genes, study the functional consequences of these mutations using cell models and zebrafish, and use these very convenient models to test drugs and molecules potentially capable of rescuing the neurological phenotype. The findings may also enhance our understanding of common neurological disorders, also featuring axonal and/or cerebellar degeneration.

The LIGENAX project is conducted in collaboration between four teams:
- Université Bordeaux 1, UMR1067 (Pr. P. Babin, Partner N°1, coordinator),
- Université Victor Segalen Bordeaux 2, EA4137, (Dr. C. Goizet, Partner N°2),
- INSERM U975, Hôpital de la Pitié-Salpêtrière, Paris, (Dr. G. Stevanin, Partner N°3).
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg (Pr. M. Koenig, Partner N°4).

Partners N°2, 3, and 4 have a highly-recognized expertise in human and medical genetics. These partners have been working for many years on identifying mutations correlated with the occurrence of spinocerebellar degenerative disorders. Partners N°2 and 3 focused on HSP and Partner N°4 on CA. Their joint work has resulted in publications in top-level scientific journals. Partner N°1 is an expert on the lipid metabolism, including humans, as well as developmental biology, comparative genomics, and neuroscience, and use the zebrafish model for his work. He collaborated during the last year with Partners N°2 and 3 on lipid genes involved on HSP and obtained preliminary functional data by using the zebrafish model.

The consortium LIGENAX members have a strong complementary expertise in human and medical genetics including neurogenetics (Stevanin G., DR2 INSERM; Durr A., PH; Brice A., PU-PH; Koenig M., PU-PH; Goizet C., AP-PH), molecular and cell biology (Coupry I., CR1 INSERM; Darios F., CR1 INSERM), and developmental biology, comparative and functional genomics, lipid metabolism and pharmacology (Babin P., PU; Knoll-Gellida A., MCU). 4 permanent technical support (engineers,/technicians) and 1 PhD student (Tesson C.) are also attached to the project . In addition to a financial support for experiments, one full time post-doc position is requested to the ANR for Tingaud-Sequeira A., a researcher with a high background in developmental biology, and the equivalent of one assistant engineer position for the 36 month-period of the project.