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

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.

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Fundacao de Amparo a Pesquisa do Estado de Sao Paulo-Centro de Estudos do Genoma Humano (FAPESP-CEPID)

Instituto Nacional de celulas-tronco em doencas geneticas (INCT)

Instituto Nacional de celulas-tronco em doencas geneticas (INCT)

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)

Muscular Dystrophy Association[MDA185410]

Muscular Dystrophy Association

Instituto Paulo Gontijo (IPG)

Instituto Paulo Gontijo (IPG)