Sptlc1, or serine palmitoyltransferase, long chain base subunit 1, is one of the two main catalytic subunits of the SPT complex. It catalyzes the first and rate-limiting step in the de novo synthesis of sphingolipids, a pathway crucial for various cellular functions, including cell membrane structure and cell signaling [4,6].

Mutations in Sptlc1 have been associated with multiple neurological disorders. In the context of amyotrophic lateral sclerosis (ALS), Sptlc1-ALS variants, which map to a transmembrane domain, impair the interaction with ORMDL proteins (negative regulators of SPT activity). This leads to increased sphingolipid synthesis and a distinct lipid signature. For example, C-terminal Sptlc1 variants cause peripheral hereditary sensory and autonomic neuropathy type 1 (HSAN1) due to the synthesis of 1-deoxysphingolipids when SPT metabolizes L-alanine instead of L-serine [1]. In juvenile ALS patients, various Sptlc1 variants have been identified, such as p.Ala20Ser, p.Ser331Tyr, p.Leu39del, and p.Leu38Arg. These mutations lead to increased SPT activity, elevated sphingolipid levels, particularly dihydro-sphingolipids, which may be involved in neurotoxicity [2,3]. Also, patients with Sptlc1 mutations tend to have an earlier age of onset and longer disease duration compared to those with other ALS-related mutations like FUS [5]. In clear cell renal cell carcinoma (ccRCC), decreased Sptlc1 expression is associated with disease progression and poor survival, suggesting it may function as a tumor suppressor [4]. In adult bone marrow cells, deletion of Sptlc1 (a form of loss-of-function similar to KO models) results in defective myeloid differentiation due to ER stress caused by perturbed sphingolipid metabolism [6].

In summary, Sptlc1 is essential for sphingolipid synthesis, which impacts multiple biological processes. Studies, including those mimicking KO-like effects in cell or animal models, have revealed its significance in neurological disorders such as ALS and HSAN1, as well as in cancer (ccRCC) and myeloid differentiation. Understanding Sptlc1 function through these model-based research approaches provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Lone, Museer A, Aaltonen, Mari J, Zidell, Aliza, Shoubridge, Eric A, Hornemann, Thorsten. 2022. SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins. In The Journal of clinical investigation, 132, . doi:10.1172/JCI161908. https://pubmed.ncbi.nlm.nih.gov/35900868/

2. Lone, Museer A, Zeng, Sen, Bourquin, Florence, Zhang, Ruxu, Hornemann, Thorsten. 2023. SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS. In Biochimica et biophysica acta. Molecular and cell biology of lipids, 1868, 159359. doi:10.1016/j.bbalip.2023.159359. https://pubmed.ncbi.nlm.nih.gov/37348646/

3. Johnson, Janel O, Chia, Ruth, Miller, Danny E, Zollino, Marcella, Zucchi, Elisabetta. . Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis. In JAMA neurology, 78, 1236-1248. doi:10.1001/jamaneurol.2021.2598. https://pubmed.ncbi.nlm.nih.gov/34459874/

4. Zhu, Wen-Kai, Xu, Wen-Hao, Wang, Jun, Zhang, Hai-Liang, Ye, Ding-Wei. 2019. Decreased SPTLC1 expression predicts worse outcomes in ccRCC patients. In Journal of cellular biochemistry, 121, 1552-1562. doi:10.1002/jcb.29390. https://pubmed.ncbi.nlm.nih.gov/31512789/

5. Wang, Peishan, Wei, Qiao, Li, Hongfu, Wu, Zhi-Ying. 2023. Clinical feature difference between juvenile amyotrophic lateral sclerosis with SPTLC1 and FUS mutations. In Chinese medical journal, 136, 176-183. doi:10.1097/CM9.0000000000002495. https://pubmed.ncbi.nlm.nih.gov/36801857/

6. Parthibane, Velayoudame, Acharya, Diwash, Srideshikan, Sargur Madabushi, Keller, Jonathan R, Acharya, Jairaj K. . Sptlc1 is essential for myeloid differentiation and hematopoietic homeostasis. In Blood advances, 3, 3635-3649. doi:10.1182/bloodadvances.2019000729. https://pubmed.ncbi.nlm.nih.gov/31751474/