Sptlc1-flox Mouse

Sptlc1, serine palmitoyltransferase, long chain base subunit 1, is a key subunit of serine palmitoyltransferase (SPT). SPT catalyzes the first step in the de novo synthesis of sphingolipids (SLs), a pathway crucial for maintaining cellular membrane integrity, cell signaling, and various biological processes [1,2,3,4,5,6,7,8].

Mutations in Sptlc1 are associated with several neurological disorders. In particular, certain Sptlc1-ALS variants that map to a transmembrane domain and interact with ORMDL proteins (negative regulators of SPT activity) lead to increased SL synthesis and a distinct lipid signature due to impaired ORMDL binding to the holoenzyme complex [1]. C-terminal Sptlc1 variants cause peripheral hereditary sensory and autonomic neuropathy type 1 (HSAN1) as SPT metabolizes L-alanine instead of L-serine, forming 1-deoxysphingolipids (1-deoxySLs) [1]. Limiting L-serine availability in Sptlc1-ALS-expressing cells can shift the SL profile from an ALS-like to an HSAN1-like signature [1]. Also, Sptlc1 mutations are linked to juvenile amyotrophic lateral sclerosis (ALS), often presenting with early age of symptom onset, muscular weakness, atrophy, and other related symptoms [2,3,4]. Some Sptlc1 mutations associated with juvenile ALS may disrupt the normal homeostatic regulation of SPT [5]. In Sptlc1-related disorders, sphingolipidomic analysis shows co-existence of neurotoxic deoxy-sphingolipids with an excess of canonical SPT products [8].

In conclusion, Sptlc1 is essential for sphingolipid synthesis. Studies on Sptlc1-related mutations in the context of neurological disorders, especially ALS and HSAN1, have provided insights into the role of Sptlc1-mediated sphingolipid metabolism in these diseases. Understanding Sptlc1 function through research on its mutations can potentially offer new therapeutic strategies for these neurological conditions.