Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients

Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients

Author Mitne-Neto, Miguel Google Scholar
Machado-Costa, Marcela Autor UNIFESP Google Scholar
Marchetto, Maria C. N. Google Scholar
Bengtson, Mario H. Google Scholar
Joazeiro, Claudio A. Google Scholar
Tsuda, Hiroshi Google Scholar
Bellen, Hugo J. Google Scholar
Silva, Helga Cristina Almeida da Autor UNIFESP Google Scholar
Oliveira, Acary S. B. Autor UNIFESP Google Scholar
Lazar, Monize Google Scholar
Muotri, Alysson R. Google Scholar
Zatz, Mayana Google Scholar
Institution Univ Calif San Diego
Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Salk Inst Biol Studies
Scripps Res Inst
Baylor Coll Med
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.
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Instituto Nacional de celulas-tronco em doencas geneticas (INCT)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Muscular Dystrophy Association
Instituto Paulo Gontijo (IPG)
Grant number Muscular Dystrophy Association: MDA185410
Date 2011-09-15
Published in Human Molecular Genetics. Oxford: Oxford Univ Press, v. 20, n. 18, p. 3642-3652, 2011.
ISSN 0964-6906 (Sherpa/Romeo, impact factor)
Publisher Oxford Univ Press
Extent 3642-3652
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000294442200010

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