Low VAPB Protein Levels May Be Cause for Inherited ALS

Headshot Dr. Alysson R. MuotriPublished in the June, 2011 issue of Human Molecular Genetics, Alysson R. Muotri, Ph.D. Assistant Professor at UC San Diego’s Department of Pediatrics and Cellular and Molecular Medicine, reported evidence of reduced levels of the VAPB protein which may play a central role in causing inherited amyotrophic lateral sclerosis (ALS).

Using induced pluripotent stem cells (iPSCs) derived from the skin cells of patients with a familial form of ALS called ALS8, Muotri et al. were able to create motor neurons that provided a novel in vitro model of the disease. This new stem cell model for ALS8 allowed the researchers to track the mutated VAPB gene during differentiation in order to determine what factors may contribute to the development of inherited ALS.

The finding suggests reduced VAPB protein levels may be a key to the development of ALS8 and perhaps other forms of the disease as well, including sporadic or non-hereditary ALS, where reduced VAPB protein levels have also been documented, said Muotri.

“The VAPB protein is involved in many cellular processes, so it seems likely it contributes to the pathogenesis of other forms of ALS,” Muotri said. “We don’t yet know how the loss of VAPB [protein] is involved in causing familial or sporadic ALS, but the new ability to study this disease in human cells provides an unprecedented opportunity to answer that question, to develop new early diagnostic tools and to identify new targets for future drugs and therapies.”

Co-authors of the study are Miguel Mitne-Neto, UCSD Department of Pediatrics/Rady Children’s Hospital-San Diego, UCSD Department of Cellular and Molecular Medicine and Human Genome Research Center, University of Sao Paulo; Marcela Machado-Costa, Helga A.C. Silva and Acary S.B. Oliveira, Federal University of Sao Paulo, Paulista School of Medicine; Maria C.N. Marchetto, Salk Institute for Biological Studies; Mario H. Bengtson and Claudio A. Joazeiro, Department of Cell Biology, The Scripps Research Institute; Hiroshi Tsuda and Hugo J. Bellen, Department of Molecular and Human Genetics, Baylor College of Medicine; Monize Lazar and Mayana Zatz, Human Genome Research Center, Department of Genetic and Evolutive Biology, University of Sao Paulo

Funding for this research came from the Muscular Dystrophy Association.

About ALS

Amyotrophic lateral sclerosis is a rapidly progressive, invariably fatal neurological disease that attacks the neurons responsible for controlling voluntary muscle movement. It does not generally impair cognitive function. An estimated 20,000 to 30,000 Americans have ALS, with 5,000 new cases diagnosed each year. ALS strikes most commonly between the ages of 40 and 60, affecting men more often than women, but with no distinction of race or ethnic background. In 90 percent of all ALS cases, the disease appears to occur randomly without clearly associated risk factors. Ten percent of cases are inherited, due to gene mutations.

Scientific Contact: Alysson R. Muotri, Ph.D. Assistant Professor, Department of Pediatrics, UC San Diego School of Medicine/Rady Children's Hospital, Dept. Cellular & Molecular Medicine, and UC San Diego Stem Cell Program muotri@ucsd.edu

Article written by Shivani Singh, Sr. Writer, Dept of Pediatrics, UC San Diego, Rady Children’s Hospital-San Diego