SPTLC1 Mutations Associated with Early Onset Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder characterized by selective degeneration of lower and upper motor neurons leading to progressive muscle weakness, swallowing difficulties, and respiratory insufficiency that ultimately causes death usually within 2–5 years of diagnosis. The majority of ALS cases occur sporadically, but a significant number (>10%) display Mendelian inheritance. Very recently, four unique de novo or dominantly inherited SPTLC1 mutations associated with early childhood‐onset ALS without clinical sensory involvement have been identified in eight independent families. SPTLC1 encodes a subunit of serine palmitoyltransferase (SPT), the committed and rate‐limiting enzyme of sphingolipid synthesis. The ALS mutations flank the first membrane spanning domain of SPTLC1, which is not required for ER targeting, association with the SPTLC2 and ssSPT subunits, or enzymatic activity. Rather, this domain is critical for binding of the ORMDL proteins that negatively regulate SPT. This suggested that the SPTLC1 mutations might interfere with homeostatic regulation of SPT and that elevated de novo sphingolipid synthesis could underlie the ALS disease pathology. Our studies reveal that these highly penetrant SPTLC1 mutations do indeed abrogate negative regulation of SPT by the ORMDL proteins and result in elevated levels of sphingolipids. Using cultured cells, patient fibroblasts, iPSC‐induced MNs, and mouse models, we are investigating the importance of ORMDL regulation in the maintenance of sphingolipid homeostasis and the mechanisms responsible for sphingolipid mediated motor neuron death. Significantly, the ALS SPTLC1 mutations confer disease pathology by a distinctly different mechanism than the previously characterized SPTLC1 and SPTLC2 mutations associated with hereditary sensory and autonomic neuropathy type 1 (HSAN1). Whereas the ALS mutations result in elevated levels of canonical sphingolipids, the HSAN1 mutations, which compromise amino acid substrate selectivity of SPT, cause accumulation of atypical deoxy‐sphingoid bases that are implicated in neuronal cell death.