ALS Briefs: Serotonergic Neurons and Counteracting Problematic Proteins

Nerve cells called serotonergic neurons degenerate in amyotrophic lateral sclerosis (ALS) and may influence the ALS disease process, an international research team has reported. In particular, the loss of these specialized cells appears to be linked to increased muscle tone or tightness (spasticity).

Among other functions, serotonergic neurons are responsible for the production of serotonin, a neurotransmitter associated with feelings of well-being and happiness.

In a study of seven people with ALS compared to six control subjects without ALS, the researchers showed that serotonin-secreting neurons degenerate in ALS.

Next, they determined that levels of serotonergic neurons decreased both before and after disease onset in mice with an ALS-like disease. In addition, the researchers noted that serotonin levels were lower during times of increased spasticity in mice. When the mice were treated with a drug called cyproheptadine (brand name Periactin), spasticity was almost completely eliminated. (Cyproheptadine blocks serotonin receptors, which are the docking sites for serotonin.)

Note: Cyproheptadine belongs to a class of drugs called antihistamines, and is often used to treat allergy symptoms. It can cause side effects including dry mouth, nose and throat; drowsiness; dizziness; nausea; headache; muscle weakness; difficulty urinating; vision problems and nervousness.

The researchers suggest that a clinical trial is warranted to assess cyproheptadine in ALS-related spasticity in humans.

The new findings, which were published online Oct. 31, 2012, in Brain, could help pinpoint new targets at which to aim therapies for spasticity in people with ALS.

Preventing protein aggregation with a ‘hydrogen peroxide scavenger’

Mistranslation, which occurs when genetic instructions are incorrectly decoded during the protein-manufacturing process, may cause proteins to misfold or to inappropriately assemble into clumps known as aggregates in ALS (with or without ALS-causing DNA mutations).

Now, a research team at Yale University in New Haven, Conn., has identified a possible method to prevent mistranslation using a protein called alkyl hydroperoxide reductase subunit F (AHPF).

AHPF is known to protect against the harmful effects of hydrogen peroxide, a chemical that is produced and used by cells for a variety of functions, but which is dangerous to DNA and other proteins at high levels.

In the common bacteria E. coli, the researchers found that AHPF reduced protein aggregation that was triggered by administration of an antibiotic called streptomycin.

It’s not yet known whether the method will work in other kinds of cells.

The findings were published online Nov. 1, 2012, in Molecular Cell. (See Protein Aggregation Caused by Aminoglycoside Action Is Prevented by a Hydrogen Peroxide Scavenger.)

Suppressing TDP43 toxicity through inhibition of DBR1

Scientists studying the genetics of the tiny, one-celled organism called baker's yeast have identified a potential target for ALS drug development: RNA lariat debranching enzyme (DBR1).

Inhibition of DBR1, the investigators found, can suppress the cellular toxicity caused by abnormal TDP43 protein, which is found in degenerating motor neurons (muscle-controlling nerve cells) in most people with ALS that isn’t caused by mutations in the SOD1 gene.

TDP43 normally is found in the cell nucleus, where it is involved in RNA processing (the chemical step that precedes protein-building). In ALS, however, TDP43 mislocates to the main cell compartment called the cytoplasm and forms into aggregates. Although scientists aren’t yet sure how TDP43 confers toxicity to motor neurons, several possibilities exist:

  • TDP43 aggregates may sequester other proteins involved in RNA processing, keeping them from performing their normal functions and leading to catastrophic changes in RNA metabolism;
  • normal TDP43 function in the nuclei of motor neurons may be lost, causing widespread dysregulation of an important part of the protein-building process called splicing; or
  • abnormal TDP43 protein might interfere with the function of normal TDP43.

The investigators found that reducing DBR1 in both human and rat motor neurons reduced TDP43-mediated toxicity. They next want to try blocking DBR1 function in animal models of ALS. If successful, the use of inhibitors able to block DBR1 could be a potential therapeutic approach for humans with the disease.

"Even though yeast and humans are separated by a billion years of evolution, we were able to use the power of yeast genetics to identify an unexpected potential drug target for ALS," study team member Aaron Gitler, an associate professor at Stanford University School of Medicine, said in a press release.

The research team published its findings online Oct. 28, 2012, in Nature Genetics. See Inhibition of RNA Lariat Debranching Enzyme Suppresses TDP43 Toxicity in ALS Disease Models.

Using antibodies to counteract misfolded protein

Detection of misfolded SOD1 protein can be accomplished by employing antibodies to act as molecular "magnets." (Antibodies are proteins produced by the immune system that detect and destroy bacteria, viruses and other foreign invaders. They also can be used by scientists to detect specific proteins.)

Amorfix Life Sciences in Ontario, Canada, reported in a press release Nov. 7, 2012, that anti-SOD1 antibodies developed by the company are being used by Serge Przedborski, professor of neurology and pathology at Columbia University in New York, to investigate the ALS disease processes and progression.

Przedborski is using the antibodies to identify nervous system cells that generate misfolded SOD1 and to investigate the misfolded protein's toxic effects on motor neurons. Ultimately, the hope is to use the anti-SOD1 antibodies to block toxicity and protect motor neurons.

Amorfix also reported at the ALS Therapy Development Institute Leadership Summit on Nov. 1, 2012, that it has licensed its antibody targets against misfolded SOD1 protein to multinational biotechnology company Biogen Idec, headquartered in Weston, Mass., for the development of antibody-based therapeutics, and to Pan Provincial Vaccine Enterprise (PREVENT) for the development of vaccines.

In addition, Amorfix is developing a blood test to be used as a diagnostic tool for the early detection of ALS, based on the detection and measurement of misfolded SOD1 present in blood.

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