Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders

Abstract

Motor neuron diseases and peripheral neuropathies are heterogeneous groups of neurodegenerative disorders that manifest with distinct symptoms due to progressive dysfunction or loss of specific neuronal subpopulations during different stages of development. A few monogenic, neurodegenerative diseases associated with primary metabolic disruptions of sphingolipid biosynthesis have been recently discovered. Sphingolipids are a subclass of lipids that form critical building blocks of all cellular and subcellular organelle membranes including the membrane components of the nervous system cells. They are especially abundant within the lipid portion of myelin. In this review, we will focus on our current understanding of disease phenotypes in three monogenic, neuromuscular diseases associated with pathogenic variants in components of serine palmitoyltransferase, the first step in sphingolipid biosynthesis. These include hereditary sensory and autonomic neuropathy type 1 (HSAN1), a sensory predominant peripheral neuropathy, and two neurodegenerative disorders: juvenile amyotrophic lateral sclerosis affecting the upper and lower motor neurons with sparing of sensory neurons, and a complicated form of hereditary spastic paraplegia with selective involvement of the upper motor neurons and more broad CNS neurodegeneration. We will also review our current understanding of disease pathomechanisms, therapeutic approaches, and the unanswered questions to explore in future studies.

Keywords: Serine palmitoyltransferase; amyotrophic lateral sclerosis; hereditary sensory and autonomic neuropathy; hereditary spastic paraplegia; sphingolipid biosynthesis.

Fig. 1

Serine palmitoyltransferase catalyzes the first and rate-limiting step in sphingolipid biosynthesis. (A) Condensation of L-Serine and fatty acyl-CoA (FA-CoA—commonly palmityol-CoA) forms 3-KDS, which is reduced to form dihydrosphingosine (dhS). N-acylation of dhS by different isoforms of ceramide synthases (CerS) forms dihydroceramides (dhCer), which are then desaturated to form ceramides (Cer). There is considerable diversity in the acyl chain length (R) of ceramides. Myriocin is a potent inhibitor of SPT. Fumonisin B1 inhibits CerS. DES = dihydroceramide desaturase (B) The multistep biosynthesis of ceramides from serine and fatty acyl-CoAs primarily occurs in the endoplasmic reticulum and its associated membranes (red). Ceramides are transported to the Golgi (blue) by ceramide transport protein (CERT) or by vesicular transport, where they serve as substrates for synthesis of higher order sphingolipids. Glucosylceramides (GlcCer) are synthesized by glucosylceramide synthase (GCS) and sphingomyelins (SMs) are synthesized by sphingomyelin synthases. Sph = sphingosine; S1P = sphingosine-1-phosphate. (C) The cryo-EM structure of SPT shows its organization into a dimer of heterotetramers (SPTLC1, SPTLC2, ORMDL3, and small subunit of SPT A are shown). The disease causing variants that lead to hereditary sensory and autonomic neuropathy type 1 (HSAN1), juvenile amyotrophic lateral sclerosis (jALS), or a complicated form of HSP (cHSP) are highlighted. In general, variants that cluster near the active site (PLP binding site), in SPTLC1 or SPTLC2, are usually associated with HSAN1 whereas those variants that affect the transmembrane domains of SPTLC1 or SPTSSA or intermembrane domain of SPTLC2 are more likely to cause jALS or cHSP. SPTLC1 S331 residue interacts both with ORMDLs and is near the active site. Substitutions at this residue typically cause a mixed phenotype of sensory neuropathy and motor neuron disease. Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/).