MOTOR NEURON DISORDERS AND NEUROPATHIES: EP.245 Characterization of a novel form of ALS associated with changes in the sphingolipid metabolism

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons characterized by severe muscle wasting, leading eventually to paralysis and death. Majority of ALS cases occur sporadically, however increasing number of cases are caused by pathogenic genetic variants with a Mendelian inheritance. Mutations in SPTLC1 subunit of the enzyme Serine-Palmitoyltransferase (SPT) were identified and associated with childhood-onset ALS. SPT catalyzes the first rate-limiting step in de-novo sphingolipid synthesis. Nine non-related families with six novel dominant mono-allelic pathogenic variants in SPTLC1 were associated with this condition. All ALS mutations map to Exon-2, encoding the SPTLC1 transmembrane domain. One of the identified mutations affects the splice site leading to an in-frame deletion of the whole exon-2. Several SPT mutations are linked to HSAN1, a predominantly sensory neuropathy that is caused by pathological levels of neurotoxic 1-deoxysphingolipids. Analysis of sphingolipid profiles in SPT-ALS patient plasma revealed distinct sphingolipid profile, that was associated with a significant increase in certain sphingolipid species but the absence of 1-deoxysphingolipids. This project aims to understand how these observed perturbances in the SL homeostasis lead to ALS and whether the observed metabolic changes can be corrected therapeutically using either a pharmacological or genetic approach. In-depth analysis of plasma lipid profiles and cells is being performed. We will generate iPSCs cells from patient fibroblasts followed by their differentiation into sensory and motor neurons. The cell models will be used to get an insight into the underlying patho-mechanism and to test putative therapeutic approaches including the modulation of the sphingolipid metabolism by pharmacological SPT inhibitors, substrate deprivation, and genetic correction of the aberrant SPTLC1 allele or silencing or its transcript.