The work, published in the June 2011 online issue of the journal Human Molecular Genetics, could help scientists overcome a major hurdle in the study and treatment of ALS, an incurable neuromuscular disorder also known as Lou Gehrig's disease. ALS is universally fatal, with a median age of onset of 55 years and survival of two to five years after symptoms appear. Past research efforts have long been stymied by difficulties in translating successful drug tests in animal models of ALS to humans.
"There is an urgent need for ALS human models that can be translated into clinical trials to verify therapeutic targets in the human genetic background," said Alysson R. Muotri, PhD, assistant professor in the UCSD Departments of Pediatrics and Cellular and Molecular Medicine, and one of the study's senior authors. "Rodents have been used in the past and still have a critical impact in unveiling the complexity of ALS, but the vast majority of drugs that have demonstrated efficacy in rodent models have not done the same in preclinical and clinical human trials."
In the new work, Muotri and colleagues turned to iPSCs derived from the skin cells of patients with a familial form of ALS called ALS8 to create motor neurons that provided a novel in vitro model of the disease. iPSCs from ALS patients have been described before, but finding cellular and molecular phenotypes has proved to be a continuing challenge. The use of a familial form of ALS offered an advantage since the mutated gene could be tracked during motor neuron differentiation.
"We don't know what causes most cases of ALS, but for roughly 10 percent of patients with ALS, the disease is the result of inherited genetic mutations," Muotri said. "One of these familial forms is ALS8, which results from mutations in the VAPB gene. Using iPSCs from several patients from two independent families, we found that VAPB protein levels are reduced in ALS8-derived motor neurons compared to similar cells from non-carrier siblings of ALS8 patients."
Muotri said 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.
"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 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.
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.
Scott LaFee | EurekAlert!
Further reports about: > B protein > Cellular > Genom > Genome Research > Human Genome Research > Human vaccine > Molecular Target > Stem cell innovation > UCSD > VAPB > cellular process > diagnostic tool > gene mutation > genetic mutation > human cell > protein levels > risk factor > skin cell > synthetic biology
Brought to light – chromobodies reveal changes in endogenous protein concentration in living cells
21.09.2018 | NMI Naturwissenschaftliches und Medizinisches Institut an der Universität Tübingen
A one-way street for salt
21.09.2018 | Julius-Maximilians-Universität Würzburg
The building blocks of matter in our universe were formed in the first 10 microseconds of its existence, according to the currently accepted scientific picture. After the Big Bang about 13.7 billion years ago, matter consisted mainly of quarks and gluons, two types of elementary particles whose interactions are governed by quantum chromodynamics (QCD), the theory of strong interaction. In the early universe, these particles moved (nearly) freely in a quark-gluon plasma.
This is a joint press release of University Muenster and Heidelberg as well as the GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt.
Then, in a phase transition, they combined and formed hadrons, among them the building blocks of atomic nuclei, protons and neutrons. In the current issue of...
Thin-film solar cells made of crystalline silicon are inexpensive and achieve efficiencies of a good 14 percent. However, they could do even better if their shiny surfaces reflected less light. A team led by Prof. Christiane Becker from the Helmholtz-Zentrum Berlin (HZB) has now patented a sophisticated new solution to this problem.
"It is not enough simply to bring more light into the cell," says Christiane Becker. Such surface structures can even ultimately reduce the efficiency by...
A study in the journal Bulletin of Marine Science describes a new, blood-red species of octocoral found in Panama. The species in the genus Thesea was discovered in the threatened low-light reef environment on Hannibal Bank, 60 kilometers off mainland Pacific Panama, by researchers at the Smithsonian Tropical Research Institute in Panama (STRI) and the Centro de Investigación en Ciencias del Mar y Limnología (CIMAR) at the University of Costa Rica.
Scientists established the new species, Thesea dalioi, by comparing its physical traits, such as branch thickness and the bright red colony color, with the...
Scientists have succeeded in observing the first long-distance transfer of information in a magnetic group of materials known as antiferromagnets.
An international team of researchers has mapped Nemo's genome, providing the research community with an invaluable resource to decode the response of fish to...
21.09.2018 | Event News
03.09.2018 | Event News
27.08.2018 | Event News
21.09.2018 | Physics and Astronomy
21.09.2018 | Life Sciences
21.09.2018 | Event News