ALS: Protein in the repository

19. November 2012
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In amyotrophic lateral sclerosis, protein deposits lead to the demise of motor neurons. Causal therapy is indeed not currently possible. Researchers have however discovered several Achilles heels.

Amyotrophic lateral sclerosis (ALS) has many faces: Jörg Immendorff (1945-2007), one of the most famous artists of contemporary Germany, died from it and the British astrophysicist Stephen Hawking has been fighting for decades against this disease. Normally ALS starts rather quietly with declining strength, with problems in holding a pen or with frequent stumbling. Later there comes severe muscle paralysis of the arms or legs; sufferers can no longer move without the help of others. Finally, they need technological assistance with speaking and breathing. Within three to five years the disease leads to death, most commonly due to pneumonia as a consequence of dysphagia. Nationwide in Germany, about 8,000 people are suffering from ALS, and an estimated 2,000 patients die each year because of it. There is fortune in Stephen Hawking’s misfortune: in his case, his body met with a juvenile form that progresses extremely slowly.

En-masse nerve death

At a molecular level more and more nerves perish with ALS. The following symptoms can be attributed to loss of function of the first and second motor neurons: spastic paralysis degrades fine motor skills, slows movements and make speaking or swallowing impossible in later stages of the disease. In parallel, the body metabolises muscles and muscle cramps occur. Researchers have not been able to determine the exact mechanisms – it has repeatedly been necessary to revise hypotheses.

Mysterious Causes

For a long time the textbook view has been that in ALS endosomes and mitochondria move only in a restricted manner along the axons. The result: nerve cells perish. Researchers have now found evidence that deficits in axonal transport of organelles and axonal degeneration are independent of one another. They investigated ALS mice for this reason using time-lapse microscopy. Fibroblast growth factor (FGF-2) has to also go through reassessment in the future. The protein, being a neurotrophic factor, is important for the development of nerve cells. Until now, scientists had assumed that FGF-2 has a positive effect on the disease process. Mice with ALS, however, survived longer if they were not able to produce the factor. As a therapeutic option FGF-2 is ruled out.

Many strategies, little clarity

In patients with familial ALS, which is approximately ten percent, human geneticists found mutations in the UBQLN2 gene. This encodes for Ubiquilin-2, a key molecule in the recycling of damaged proteins. By way of errors in genetic tissue, non-functional forms arise and the body stores proteins actually which are labelled for degradation in the nerve cells. Similar accumulations occur in patients without UBQLN2 mutations. TDP-43 carries information for a protein with regulatory functions. Via alternative splicing, that is variable processing of ribonucleic acids (mRNAs), it manages the activity of several genes. Mutations in the TDP-43 gene lead to nonfunctional proteins which accumulate in neurons and cause their demise.

Not least of all, a further gene C9ORF72 comes into play. The associated enzyme superoxide dismutase regulates inflammation by influencing Capase-1 activities. The Capase in return splits interleukin-1β (IL-1β) from its precursors. In ALS patients a high level of Capase-1 was able to be detected. The innovative approach now is to block IL-1β receptors. In mice at least the disease state improved and life expectancy increased. Beyond that stem cells carry high expectations. Researchers at the University of Bochum succeeded in isolating stem cells from the spinal cord of mice and transforming them into immature nerve cells. Their hope: because they are in an early development phase, they can be better integrated into neural networks. A long time will pass before this strategy reaches the point of being a benefit for patients.

Perplexity in the clinic

Currently the situation looks rather bad: If neurologists through finding specific “El-Escorial Criteria” diagnose ALS without doubt, they are not able to do much. The focus of the drug therapy is Riluzole. This benzothiazole is characterised by its neuroprotective effect. Patients benefit in two ways: the progression slows, and the average lifetime extends by three months. Otherwise the guideline mainly mentions symptomatic approaches, such as with occurance of convulsions (carbamazepine, quinine sulfate, etc.) or excessive salivation (amitriptyline, scopolamine, etc). If pathological laughter or crying develops, colleagues reach for selective serotonin reuptake inhibitors (citalopram, fluvoxamine, among others). Additionally there are also measures against aspiration pneumonia, i.e. physical therapies, a reduction in salivary flow, as well as early antibiosis in instances of infection. Sooner or later various tools such as electric wheelchairs or respirators are also required.

First aid for nerve cells

Now colleagues have great expectations for dexpramipexole, the R-enantiomer of the well-known Parkinson’s disease drug pramiprexol. This medicine protects neurons by normalising their energy metabolism. After a phase II study with more than 100 patients yielded indicators showing ALS was slowing, a placebo-controlled, double-blind phase III study with more than 800 affected people followed. In addition, the European Medicines Agency (EMA) approved an agent as an Orphan Drug for ALS: S-apomorphine passes through the blood-brain barrier and leads to higher Nrf2 levels. Scientists surmise that Nrf2 can neutralise toxic effects of reactive oxygen species (ROS) in the nervous system. It often happens that a very simple trick can readily help.

Wanted pounds

While the negative consequences of being overweight are commonly and generally known, an American working project with 400 study participants caused people to sit up and take notice particularly with regard to ALS. Patients with BMI-figures of between 30 and 35 had the highest chance of survival. This in all likelihood derives from increased energy consumption. The German guideline recommends, apart from a high caloric diet, the early application of percutaneous endoscopic gastrostomy (PEG). When doing so, the respiratory situation of patients must be given attention, so as to not take any risks.

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