title: Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia.
abstract: Spastic paraplegia 46 refers to a locus mapped to chromosome 9 that accounts for a complicated autosomal-recessive form of hereditary spastic paraplegia (HSP). With next-generation sequencing in three independent families, we identified four different mutations in GBA2 (three truncating variants and one missense variant), which were found to cosegregate with the disease and were absent in controls. GBA2 encodes a microsomal nonlysosomal glucosylceramidase that catalyzes the conversion of glucosylceramide to free glucose and ceramide and the hydrolysis of bile acid 3-O-glucosides. The missense variant was also found at the homozygous state in a simplex subject in whom no residual glucocerebrosidase activity of GBA2 could be evidenced in blood cells, opening the way to a possible measurement of this enzyme activity in clinical practice. The overall phenotype was a complex HSP with mental impairment, cataract, and hypogonadism in males associated with various degrees of corpus callosum and cerebellar atrophy on brain imaging. Antisense morpholino oligonucleotides targeting the zebrafish GBA2 orthologous gene led to abnormal motor behavior and axonal shortening/branching of motoneurons that were rescued by the human wild-type mRNA but not by applying the same mRNA containing the missense mutation. This study highlights the role of ceramide metabolism in HSP pathology.
authors: Unité Mixte de Recherche S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Pitie-Salpêtrière Hospital, Université Pierre et Marie Curie (Paris 6), Paris, France.
authors: Elodie
authors: E
authors: Martin
authors: Rebecca
authors: R
authors: Schüle
authors: Katrien
authors: K
authors: Smets
authors: Agnès
authors: A
authors: Rastetter
authors: Amir
authors: A
authors: Boukhris
authors: José L
authors: JL
authors: Loureiro
authors: Michael A
authors: MA
authors: Gonzalez
authors: Emeline
authors: E
authors: Mundwiller
authors: Tine
authors: T
authors: Deconinck
authors: Marc
authors: M
authors: Wessner
authors: Ludmila
authors: L
authors: Jornea
authors: Andrés Caballero
authors: AC
authors: Oteyza
authors: Alexandra
authors: A
authors: Durr
authors: Jean-Jacques
authors: JJ
authors: Martin
authors: Ludger
authors: L
authors: Schöls
authors: Chokri
authors: C
authors: Mhiri
authors: Foudil
authors: F
authors: Lamari
authors: Stephan
authors: S
authors: Züchner
authors: Peter
authors: P
authors: De Jonghe
authors: Edor
authors: E
authors: Kabashi
authors: Alexis
authors: A
authors: Brice
authors: Giovanni
authors: G
authors: Stevanin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005190:Family; D005260:Female; D005962:Glucosylceramidase; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D059906:Neuroimaging; D010375:Pedigree; D015419:Spastic Paraplegia, Hereditary / Q000201:enzymology* / Q000235:genetics*; D055815:Young Adult; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics*; D001617:beta-Glucosidase / Q000235:genetics*
chemical_list: D029961:Zebrafish Proteins; D001617:beta-Glucosidase; C517537:GBA2 protein, human; C579440:GBA2 protein, zebrafish; D005962:Glucosylceramidase