Causes Of Als

Human-Cell-Derived Model of ALS Provides a New Way to Study the Majority of Cases

Newswise — For decades, scientists have studied a laboratory mouse model that develops signs of the paralyzing disease amyotrophic lateral sclerosis (ALS) as they age. In a new study appearing in Nature Biotechnology , investigators at Nationwide Children’s Hospital have developed a new model of ALS, one that mimics sporadic ALS, which represents about 90 percent of all cases.

ALS, commonly known as Lou Gehrig's disease, is characterized by the death of motor neurons, which are muscle-controlling nerve cells in the spinal cord. As these neurons die, the body’s voluntary muscles weaken and waste away; death within five years of diagnosis is common. Only about 10 percent of ALS cases are familial meaning the disease runs in the family. The majority of ALS cases are sporadic, with no family history.

Mutations in the SOD1 gene are found in about one-fifth of people with familial ALS, and for decades, experts have theorized that the gene holds clues to sporadic ALS. Laboratory mice carrying human SOD1 mutations develop signs of ALS as they age, and have been widely used to investigate the causes and potential treatments for the disease. At the same time, however, researchers have questioned whether SOD1 mice are useful and whether SOD1 itself is relevant for understanding sporadic ALS. While dozens of potential therapies have shown promise in the mice, most have failed in patients.

“The mouse models capture a type of familial ALS that accounts for only two percent of all cases. The field has begged for new disease models that can provide a clear window into sporadic ALS,” said senior author Brian Kaspar, PhD, principal investigator in the Center for Gene Therapy of The Research Institute at Nationwide Children’s Hospital.

Nationwide Children’s researchers attempted to develop such a model by isolating cells from patients’ spinal tissue within a few days after death.

First, the team isolated neural progenitor cells from post-mortem spinal tissue of patients with ALS. Neural progenitor cells are the “parent” cells of neurons and astrocytes, cells of the central nervous system. They then coaxed these progenitor cells to develop into astrocytes. Next, the team combined the patient-derived astrocytes with mouse motor neurons. At first, the motor neurons grew normally, but after four days, they began to degenerate. By five days, the number of motor neurons reduced by about half compared to motor neurons that had been grown with control astrocytes. Similar results were seen when the motor neurons were grown with astrocytes from a patient with familial ALS, or with a cell culture broth that had been conditioned by astrocytes from any of the ALS patients. This suggests the ALS-derived astrocytes are releasing one or more unknown toxins.

Stem Cell Model Offers Clues To Cause of Inherited ALS

An international team of scientists led by researchers at the University of California, San Diego School of Medicine have used induced pluripotent stem cells (iPSCs) derived from patients with amyotrophic lateral sclerosis (ALS) to reveal for the first time how reduced levels of a specific protein may play a central role in causing at least one inherited form of the disease.

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.

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