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A Protein Critical to the Neuromuscular Junction Found in Sera of ALS Patients

ARTICLE IN BRIEF

Researchers implicated LDL receptor-related protein 4 (LRP4) in the pathogenesis of amyotrophic lateral sclerosis. They found one in five patients in three different countries had antibodies to LRP4, a protein important to neuromuscular function.

WASHINGTON—One in five patients with amyotrophic lateral sclerosis (ALS) in three different countries were found to have antibodies to LDL receptor-related protein 4 (LRP4), a protein important to neuromuscular function. The findings point to the protein as a potential biomarker and therapeutic target for ALS, investigators reported here in April at the AAN Annual Meeting.

LRP4 is a large transmembrane protein with many binding partners, and it plays an important role in the development and function of motor neurons and neuromuscular junctions, enabling acetylcholine receptor (AChR) function. It is also important in the development and health of the axon terminal in neurons of the hippocampus, olfactory bulb, cerebellum, neocortex, and spinal cord.

A 10-nation study published last year involving many of the same lead researchers found that 19 percent of myasthenia gravis (MG) patients without antibodies to AChR or muscle specific tyrosine kinase (MuSK) did have antibodies to LRP4 — which amounts to about 3 percent of all MG patients.

The investigators reported that LRP4 antibodies were even more common in ALS patients. Using a cell-based assay based on human LRP4-expressing HEK293 cells, they reported finding antibodies in the sera of 37 of 191 (19.4 percent) of ALS patients in Greece, Italy, and Israel. The antibodies were also found in five of six anti-LRP4 seropositive cases in which CSF samples were available; the titers were similar to those found in MG patients.

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DR. JOHN TZARTOS: “ALS is a heterogeneous disease in terms of clinical phenotype and pathogenicity. As a consequence, the identification of specific biomarkers might allow subgrouping of ALS patients, allowing early and specific intervention.”

The antibodies were found in only five out of 138 patients (3.6 percent) with other neurological disorders, and not in any of 140 healthy controls.

The study author John Tzartos, MD, PhD, of the Hellenic Pasteur Institute in Athens, Greece, said detection of the antibodies could help with earlier and more tailored treatments.

“ALS is a heterogeneous disease in terms of clinical phenotype and pathogenicity,” he said. “As a consequence, the identification of specific biomarkers might allow subgrouping of ALS patients, allowing early and specific intervention.”

If LRP4 antibodies can be found at the earliest stages of ALS, “they will be a precious biomarker, because they will allow the application of early intervention strategies, hopefully before permanent damage occurs.”

He added that because ALS and MG are often confused, especially when patients exhibit bulbar symptoms, caution should be used when LRP4 antibodies are found in patients with such symptoms, so that they aren't misdiagnosed.

He noted that LRP4 is expressed in motor neurons in the brain and spinal cord and, in animal models, has been shown to play a vital role in the well-being of motor neurons. In animals, LRP4 antibodies have been shown to reduce the viability of neurons in cell cultures and to impair synaptic structures.

“The important role of LRP4 is that it [provides evidence] that the presence of anti-LRP4 antibodies in a subgroup of ALS patients may be pathogenic,” he said. “Immunosuppressive therapies have failed in ALS. However, if we concentrate the efforts in a subgroup of patients, such as this, and start from the earliest steps of the disease, we may be able to show an effect of immunosuppression in this subgroup.”

Whether LRP4 antibodies are present before symptoms appear is not yet known, although this group has detected these antibodies in three patients just four to eight months after the start of symptoms, when they had possible or probable ALS. They did end up developing ALS.

“Unfortunately it is very difficult to have sera from ALS patients before symptoms appear, but at least we are now trying to test sera as soon as the first suspicion for possible ALS appears.”

EXPERT COMMENTARY

Merit Cudkowicz, MD, MSc, chief of neurology at Massachusetts General Hospital and a professor of neurology at Harvard Medical School, said the study is important but is “just the first step.” She said that much more needs to be done to ascertain whether the antibodies are a biomarker of ALS.

She said the findings need to be explored in a much larger study with a broader group of controls, including more subjects with more disorders that “mimic” ALS. Whether LRP4 antibodies are related to disease course or clinical phenotype needs to be examined. Another question, she said, is whether the antibodies mark a subset of patients who might have an autoimmune component.

“We don't know if this is related to the disease or not,” she said. “Being different from healthy controls doesn't yet provide information on whether the antibodies are useful as biomarker.”

Richard Bedlack, MD, PhD, FAAN, an associate professor of neurology at the Duke University School of Medicine and director of the Duke ALS Clinic, agreed that more research is needed. “I think it is too early to know what this means,” he said. “There is clearly immune dysregulation — including a variety of autoantibodies — in at least some patients with ALS, but the question is whether this is a cause for, or a response to, the disease.”

Another possibility, he said, is that some of the patients might have been misdiagnosed with ALS, which is likely in cases in which a patient had a mimic not usually tested for, such as an unusual form of myasthenia gravis, that could possibly be LRP4-mediated.

EXPERTS: ON A POTENTIAL BIOMARKER FOR ALS

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DR. MERIT CUDKOWICZ said whether LRP4 antibodies are related to disease course or clinical phenotype needs to be examined. Another question, she said, is whether the antibodies mark a subset of patients who might have an autoimmune component.

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DR. RICHARD BEDLACK: “I think it is too early to know what this means. There is clearly immune dysregulation — including a variety of autoantibodies — in at least some patients with ALS, but the question is whether this is a cause for, or a response to, the disease.”

LINK UP TO MORE INFORMATION:

•. AAN Annual Meeting Abstract: LRP4 antibodies are frequent in serum and CSF from amyotrophic lateral sclerosis patients: http://bit.ly/ALS-antibodies
    •. Zisimopolou P, Evangelakou P, Tzartos J, et al. A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis http://www.sciencedirect.com/science/article/pii/S0896841113001510. J Autoimmun 2014;52:139–145.
      •. Tzartos JS, Zisimopoulou P, Rentzos M, et al. LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients http://onlinelibrary.wiley.com/doi/10.1002/acn3.26/abstract. Ann Clin Transl Neurol 2014; 1(2):80–87.
        •. Zhang B, Tzartos JS, Belimezi M, et al. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis http://archneur.jamanetwork.com/article.aspx?articleid=1150052. JAMA Neurol 2012; 69(4):445–451.