Genetics, cell biology and a novel mechanism for ALS

Disrupted homeostasis in sphingolipid synthesis causes severe ALS in young children Syeda and colleagues used an elegant combination of genetics, meticulous clinical evaluation and cell biology to demonstrate that disrupting serine palmitoyl transferase (SPT) can cause amyotrophic lateral sclerosis (ALS) in very young children.1 SPT is the initial rate-limiting step in sphingolipid biosynthesis, joining serine and palmitoyl CoA in a decarboxylating condensation reaction that ultimately creates ceramide, sphingosine, glycosphingolipids and gangliosides.2 SPT resides in the endoplasmic reticulum membrane as a dimer of two subunits, SPTLC1 and SPTLC2, which are in turn attached to two small subunits ssSPTa and ssSPTb that activate enzyme activity and orosomucoid-like proteins (ORMDLs) that repress SPT activity to ensure sphingolipid homeostasis. Resultant sphingolipids are subsequently processed through the Golgi apparatus and inserted into plasma membranes where they are involved in multiple signalling pathways including those that sometimes cause opposing effects....
Source: Journal of Neurology, Neurosurgery and Psychiatry - Category: Neurosurgery Authors: Tags: Open access Editorial commentaries Source Type: research