18 February 2014

GDNF is a new target for the treatment of parkinsonism

Glial neurotrophic factor
stops mitochondrial degeneration in Parkinson's disease

LifeSciencesToday based on MPI fur Neurobiologie materials:
Parkinson gene: Nerve growth factor halts mitochondrial degenerationIn neurodegenerative diseases, such as Parkinson's disease, thousands of nerve cells die in the brain.

Endogenous neurotrophic factors produced by the body itself, including glial neurotrophic factor (GDNF), contribute to the survival of nerve cells.

Scientists from the Max Planck Institute of Neurobiology (Max-Planck-Institutes fur Neurobiologie) in Martinsried near Munich and their colleagues have shown that GDNF (glial cell line-derived neurotrophic factor) and its Ret receptor contribute to the survival of mitochondrial cell power stations. By activating Ret receptors, mitochondrial degradation caused by the Parkinson's disease-related gene can be prevented in flies and in human cell cultures. This is an important connection, and in the future it may lead to the emergence of more effective drugs based on GDNF.

The disease, which today affects almost 280 thousand people in Germany alone, was first described by James Parkinson in his "Treatise on Trembling Paralysis" in 1817. The most striking symptom of Parkinson's disease is tremor, which, as a rule, is accompanied by progressive stiffness of movements. These symptoms are visible signs of dramatic changes in the brain: a lot of nerve cells die in the Substantia nigra (black substance) of the midbrain.

Despite almost two centuries of studying Parkinson's disease, its causes are still not completely clear. It is obvious that along with environmental factors, genetic changes also play a role in the development of the disease. Now scientists associate a number of genes with Parkinson's disease. One of these genes is PINK1, a mutation in which causes mitochondrial dysfunction. Without these "power stations", the cell cannot function normally and recover. Scientists from the Max Planck Institute of Neurobiology and their colleagues from Munich and Martinsried have established a hitherto unknown connection that prevents mitochondrial dysfunction with a mutation in the PINK1 gene.

Evolutionarily, the PINK1 gene appeared very early, and it is present in a similar form in the genome of humans, mice and flies. In the fruit fly drosophila, a mitochondrial defect caused by a mutation in the PINK1 gene manifests itself in the form of degradation of muscle fibers. It is less noticeable, but nerve cells also die in flies. Scientists have studied the molecular processes of these changes and found that the activation of Ret receptors resists muscle degeneration.

The PINK1 gene plays an important role in the development of Parkinson's disease. When this gene is suppressed, the mitochondria (green) are damaged in drosophila, after which the breakdown of muscle fibers (red) occurs. Activation of Ret receptors, which bind the neurotrophic factor GDNF in humans, counteracts muscle degeneration. (© MPI fur Neurobiologie/Klein)"This is a really interesting discovery that establishes a link between the degradation of mitochondria in Parkinson's disease and neurotrophic factors," comments the results of the study, its head, Professor Dr. Rudiger Klein (Rudiger Klein).

The Martinsrid neurobiologists are well aware of the Ret receptor.
"A few years ago, we showed in mice that nerve cells without Ret die prematurely and in increasing numbers as they age," recalls Professor Klein.

The Ret receptor is the site of interaction of the endogenous growth factor GDNF with the cell surface. In recent years, various studies have shown that the binding of GDNF to its receptor prevents the early death of nerve cells in the substantia nigra. But so far, GDNF clinical trials conducted on patients with Parkinson's disease have not revealed a distinct improvement in their condition.

However, the new results of this fundamental study suggest that through Ret/GDNF, mitochondrial metabolism can be increased and restored.

"Based on this knowledge, it is possible to make existing therapies more effective or targeted at specific groups of patients," says the first author of the article Ret rescues mitochondrial morphology and muscle degeneration of Drosophila Pink1 mutants, published in The EMBO Journal Pontus Klein, for whom this study is a work in the framework of doctoral dissertation.

Scheme from the EMBO article

This hope does not seem completely unfounded, since scientists have already established that in human cells with a mutation in the PINK1 gene, the effect of Ret/GDNF is similar to the effect observed in fruit flies. Therefore, in the future, in patients with Parkinson's disease, doctors may look for a metabolic disorder in the mitochondria. Targeted GDNF therapy may become a new approach to the treatment of patients with a positive test for mitochondrial metabolism disorder.

Portal "Eternal youth" http://vechnayamolodost.ru18.02.2014

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