Characterization of a novel form of ALS associated with changes in the sphingolipid metabolism

Dr. Museer Lone, University of Zürich

Abstract (lay summary see below)

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. While majority of ALS cases appear to occur sporadically, relatively less, however increasing number of cases are caused by pathogenic genetic variants with a Mendelian pattern of inheritance. Clinical hallmarks include progressive muscle wasting, speech and swallowing difficulties, fasciculations, altered reflexes, and spasticity. Both genotypic heterogeneity, and phenotype variability prevent elucidation of a pathophysiological mechanism. Age and site of onset, rate of progression and pattern of motor neuron degeneration vary greatly among affected individuals.
Mutations in the SPTLC1 subunit of the enzyme Serine-Palmitoyltransferase (SPT) were identified and associated with childhood-onset ALS. SPT catalyzes the first and rate-limiting step in the de novo synthesis of sphingolipids. Currently, nine non-related families with four novel dominantly acting mono-allelic pathogenic variants in SPTLC1 were associated with this condition. All ALS mutations map to Exon 2, encoding for a transmembrane domain region in SPT. One of the identified mutations affects the spice site leading to an in-frame deletion of the whole exon 2. Several SPT mutation are linked to HSAN1, a predominantly sensory neuropathy that is caused by pathological levels of an atypical and neurotoxic class of 1- deoxysphingolipids. However, a first analysis of the sphingolipid profile in plasma of the SPT-ALS patients 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. We will perform an indepth analysis of the lipid profile in plasma of the patients and comprehensive biochemical characterization of the ALS associated SPTLC1 variants. 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. 

Lay summary

Amyotrophe Lateralsklerose (ALS) ist eine fortschreitende neurodegenerative Erkrankung, die zu Muskelschwund, Lähmung und letztlich zum Tod führt. Der Pathomechanismus ist in den meisten Fällen unbekannt. Ein kleiner Teil der ALS Fälle ist mit spezifischen, vererbbaren Mutationen verbunden. Kürzlich wurden sechs neue Mutationen im SPTLC1 Gen ursächlich mit ALS im Kindesalter assoziiert. Das Gen kodiert für eine der drei Untereinheiten der Serin-Palmitoyl-Transferase, einem essentiellen Enzym bei der Bildung von Sphingolipiden. Sphingolipide sind wichtige Bausteine der Zellmembran und erste Untersuchungen haben gezeigt, dass die ALS Mutationen zu einer fehlerhaften Regulation des Sphingolipid-Stoffwechsels führen, was sich in einem charakteristisch veränderten Sphingolipid Profil im Blut der Patienten widerspiegelt. In diesem Projekt wollen wir verstehen, wie diese Veränderungen ALS auslösen können und untersuchen, ob durch eine pharmakologische oder genetische Intervention eine wirksame Therapie möglich ist.