Mayo Clinic researchers and collaborators have identified a protein expressed by immune cells that may play a key role in the development of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. The team also found that an immunomodulatory treatment that blocks the protein was able to restore motor function in preclinical models. The findings suggest that the protein, known as α5 integrin (pronounced alpha 5 integrin), is a potential therapeutic target for ALS.
The study was published in the journal Proceedings of the National Academy of Sciences.
Fatal disease
ALS is a fatal motor neuron disease. People with ALS often die within three years of diagnosis. While there have been advances in understanding ALS, there is no cure or treatment that significantly improves motor function or extends survival in those with the disease. Although loss of motor neurons is the hallmark of ALS, the immune system also is involved in most people.
The disease involves activation of immune cells, including microglial cells and macrophages, which have pro-inflammatory properties. Microglial cells are immune cells specific to the nervous system. Macrophages are general immune system “cleanup” cells that are present in the peripheral nervous system.
The research team found the protein α5 integrin, which is expressed by microglial cells and macrophages, is present in abundance in the motor system in people with ALS, including in those with a genetic cause of the disease.
“Our study found α5 integrin to be expressed in immune cells and also in blood vessels in active stages of the disease, as well as in end-stage disease,” says Shanu F. Roemer, M.D., Ph.D., a Mayo Clinic neuropathologist and co-first author of the study. The team also found that α5 integrin is not expressed in brain tissue from people without ALS or other neurodegenerative or inflammatory disorders such as Alzheimer’s disease, Progressive Supranuclear Palsy (a Parkinsonian disorder) or sepsis.
“The findings suggest α5 integrin plays a role in the pathology of ALS,” says Dr. Roemer. “Because α5 integrin appears selective to ALS and is upregulated in brain and nerve fibers outside of the spinal cord in ALS, it opens up the possibility of exploring α5 integrin as a diagnostic and treatment biomarker.”
In addition to preclinical models, the researchers examined human tissue from the Mayo Clinic ALS Brain Bank and Autopsy Program to determine the pervasiveness of α5 integrin in ALS. Dennis W. Dickson, M.D., the Robert E. Jacoby Professor of Alzheimer’s Research and a neuroscientist in Mayo Clinic’s Department of Neuroscience in Florida, directs the brain bank and also is a co-author of the study. The brain bank works closely with Bjorn Oskarsson, M.D., director of Mayo Clinic’s ALS clinic, and includes a large collection of brain and spinal cord tissue from people with ALS who donated their brains to Mayo Clinic for ALS research. The researchers used more than 100 ALS tissue samples in the study.
Possible novel pathway
The study team also explored a pathway for potential treatment. They found that a monoclonal antibody that blocks α5 integrin was able to preserve motor function in mice models. Monoclonal antibodies are synthesized immune system proteins used as a treatment for a wide range of diseases.
“Our findings showed that the antibody treatment against α5 integrin seemed to protect motor function, delay disease progression and increase survival,” says Dr. Roemer. “Taken together, the findings regarding the upregulation of α5 integrin and its response to a monoclonal antibody suggest α5 integrin may be a potential therapeutic target for modulation of neuroinflammation in ALS.”
Because several drugs exist that target other integrins for different diseases, the researchers suggest that a clinical trial to test α5 integrin as a drug target in ALS might be worthwhile. Review the study for a complete list of authors, disclosures and funding.
This article first published on Discovery’s Edge.
