title: Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients.
abstract: Amyotrophic lateral sclerosis (ALS) is an incurable neuromuscular disease that leads to a profound loss of life quality and premature death. Around 10% of the cases are inherited and ALS8 is an autosomal dominant form of familial ALS caused by mutations in the vamp-associated protein B/C (VAPB) gene. The VAPB protein is involved in many cellular processes and it likely contributes to the pathogenesis of other forms of ALS besides ALS8. A number of successful drug tests in ALS animal models could not be translated to humans underscoring the need for novel approaches. The induced pluripotent stem cells (iPSC) technology brings new hope, since it can be used to model and investigate diseases in vitro. Here we present an additional tool to study ALS based on ALS8-iPSC. Fibroblasts from ALS8 patients and their non-carrier siblings were successfully reprogrammed to a pluripotent state and differentiated into motor neurons. We show for the first time that VAPB protein levels are reduced in ALS8-derived motor neurons but, in contrast to over-expression systems, cytoplasmic aggregates could not be identified. Our results suggest that optimal levels of VAPB may play a central role in the pathogenesis of ALS8, in agreement with the observed reduction of VAPB in sporadic ALS.
authors.affiliation: University of California San Diego, School of Medicine, Department of Pediatrics/Rady Children’s Hospital San Diego, Department of Cellular & Molecular Medicine, Stem Cell Program, 9500 Gilman Dr, La Jolla, CA 92093, MC 0695, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Mitne-Neto
authors.forename: Marcela
authors.initials: M
authors.lastname: Machado-Costa
authors.forename: Maria C N
authors.initials: MC
authors.lastname: Marchetto
authors.forename: Mario H
authors.initials: MH
authors.lastname: Bengtson
authors.forename: Claudio A
authors.initials: CA
authors.lastname: Joazeiro
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuda
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
authors.forename: Helga C A
authors.initials: HC
authors.lastname: Silva
authors.forename: Acary S B
authors.initials: AS
authors.lastname: Oliveira
authors.forename: Monize
authors.initials: M
authors.lastname: Lazar
authors.forename: Alysson R
authors.initials: AR
authors.lastname: Muotri
authors.forename: Mayana
authors.initials: M
authors.lastname: Zatz
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D009154:Mutation; D010375:Pedigree; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C496748:VAPB protein, human; D033921:Vesicular Transport Proteins