title: Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy.
abstract: Mutations in enzymes involved in sphingolipid metabolism and trafficking cause a variety of neurological disorders, but details of the molecular pathophysiology remain obscure. SPTLC1 encodes one subunit of serine palmitoyltransferase (SPT), the rate-limiting enzyme in sphingolipid synthesis. Mutations in SPTLC1 cause hereditary sensory and autonomic neuropathy (type I) (HSAN1), an adult onset, autosomal dominant neuropathy. HSAN1 patients have reduced SPT activity. Expression of mutant SPTLC1 in yeast and mammalian cell cultures dominantly inhibits SPT activity. We created transgenic mouse lines that ubiquitously overexpress either wild-type (SPTLC1(WT)) or mutant SPTLC1 (SPTLC1(C133W)). We report here that SPTLC1(C133W) mice develop age-dependent weight loss and mild sensory and motor impairments. Aged SPTLC1(C133W) mice lose large myelinated axons in the ventral root of the spinal cord and demonstrate myelin thinning. There is also a loss of large myelinated axons in the dorsal roots, although the unmyelinated fibers are preserved. In the dorsal root ganglia, IB4 staining is diminished, whereas expression of the injury-induced transcription factor ATF3 is increased. These mice represent a novel mouse model of peripheral neuropathy and confirm the link between mutant SPT and neuronal dysfunction.
authors.affiliation: Day Laboratory for Neuromuscular Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, 02129, USA. amccampbell@partners.org
authors.forename: Alexander
authors.initials: A
authors.lastname: McCampbell
authors.forename: David
authors.initials: D
authors.lastname: Truong
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Broom
authors.forename: Andrew
authors.initials: A
authors.lastname: Allchorne
authors.forename: Ken
authors.initials: K
authors.lastname: Gable
authors.forename: Roy G
authors.initials: RG
authors.lastname: Cutler
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Harmon
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Dunn
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D001369:Axons / Q000473:pathology; D001522:Behavior, Animal / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005799:Genes, Dominant; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D046790:Pancreas, Exocrine / Q000473:pathology; D051102:Serine C-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D051102:Serine C-Palmitoyltransferase; C495088:Sptlc1 protein, mouse