Translating molecular pathology into a therapeutic strategy in SCA38, a newly identified form of spinocerebellar ataxia

Spinocerebellar ataxias (SCAs) include over thirty different subtypes of central nervous system diseases that affect approximately 1 in 30,000 persons. We have identified the disease gene for SCA38, a novel rare form of cerebellar ataxia associated with neuropathy. Estimated frequency of the disease is below 1% of SCAs. The disease gene encodes an enzyme involved in omega-3 fatty acids biosynthesis, whose products are reduced in patients serum. We reasoned that the administration of specific omega-3 fatty acids could ameliorate the disease symptoms in patients. Indeed, preliminary data obtained in a pilot trial on two patients, now in their 8th-month therapy, are remarkable, with an improvement of disease symptoms and quality of life, without any adverse effect. The project will develop following three aims: 1) to study disease pathways leading from mutations in ELOVL5 to ataxia. We will explore the role of mutated products on cellular function, verifying the effect on endoplasmic reticulum (where ELOVL5 is localized), Golgi, and mitochondria. 2) To establish an international collaboration that will give us the opportunity to study a mouse model lacking Elovl5, to verify if reduction of this enzyme is per se sufficient to determine neurological signs, and which is the role of this enzyme and its products in cerebellum. 3) To extend our observational clinical trial to further prove our therapeutic strategy of SCA38. Clinical SARA scores, PET neuroimages, plasma metabolic pattern and disease gene expression will be verified in at least ten SCA38 patients in a placebo conrolled trial with omega-3 fatty acids. Our project will join a molecular biology study to try to dissect spinocerebellar ataxia 38 mechanisms and a clinical trial to provide a treatment for this novel form of cerebellar degeneration. Our results may reveal useful to understand other cerebellar degenerative mechanisms.