Journal Article

Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis

Tarnopolsky, Mark, Konersman, Chamindra G., Bönnemann, Carsten G., Hu, Ying, Pourshafie, Naemeh, Le Pichon, Claire E., Moreira, Ana Lucila, Logroscino, Giancarlo, Lone, Museer A., Mohassel, Payam, Piccus, Zoe, Gangfuß, Andrea, Hornemann, Thorsten, Introna, Alessandro, Nalls, Matthew, Brady, Lauren, Brown, Robert H., Schara, Ulrike, Saade, Dimah, Brandt, Tracy, Kölbel, Heike, Pedro, Helio, Roos, Andreas, Donkervoort, Sandra, Thomas, Florian P., Foley, A. Reghan, Grunseich, Christopher, Straub, Volker, Zidell, Aliza, Ly, Cindy V., Töpf, Ana, Höke, Ahmet, Fiorillo, Chiara, Cho, Megan T., Lee, Chia-Hsueh, Neuhaus, Sarah B., Kok, Fernando, Gupta, Sita D., Connolly, Anne M., Specht, Sabine, Dunn, Teresa M., Nickolls, Alec R., Mittelmann, Eric, Saute, Jonas Alex Morales, Gable, Kenneth, Chao, Katherine R.

2021

Overview

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons with sporadic or hereditary occurrence. Age of onset, pattern of motor neuron degeneration and disease progression vary widely among individuals with ALS. Various cellular processes may drive ALS pathomechanisms, but a monogenic direct metabolic disturbance has not been causally linked to ALS. Here we show SPTLC1 variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS. We identified four specific, dominantly acting SPTLC1 variants in seven families manifesting as childhood-onset ALS. These variants disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products. Notably, this is in contrast with SPTLC1 variants that shift SPT amino acid usage from serine to alanine, result in elevated levels of deoxysphingolipids and manifest with the alternate phenotype of hereditary sensory and autonomic neuropathy. We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro. The role of primary metabolic disturbances in ALS has been elusive; this study defines excess sphingolipid biosynthesis as a fundamental metabolic mechanism for motor neuron disease. Clinical and genetic evaluation of individuals with childhood-onset amyotrophic lateral sclerosis identifies a new monogenic cause for early-onset ALS and proposes a specific metabolic mechanism leading to motor neuron disease via sphingolipid excess.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/45/287/1196 / 692/699/375/1917/1285 / Adolescent / Adult / Age / Alanine / Alleles / Amino Acid Sequence / Amino acids / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - enzymology / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Autonomic nervous system / Biomedical and Life Sciences / Biomedicine / Biosynthesis / Cancer Research / Child / Childhood / Children / CRISPR-Cas Systems / Degeneration / Female / Genes, Dominant / HEK293 Cells / Humans / Infectious Diseases / Male / Metabolic Diseases / Metabolism / Middle Aged / Molecular Medicine / Motor neuron diseases / Motor neurone disease / Mutation / Neurodegeneration / Neurodegenerative diseases / Neuropathy / Neurosciences / Palmitoyltransferase / Phenotypes / Serine / Serine C-Palmitoyltransferase - genetics / Serine C-Palmitoyltransferase - metabolism / Serine palmitoyltransferase / Sphingolipids - biosynthesis / Young Adult