Removing "garbage" from the nuclei of neurons helps with neurodegenerative diseases

Neuroscientists at Georgetown University Medical Center have obtained new data refuting the scientific dogma describing the mechanisms of development of two fatal neurodegenerative diseases – amyotrophic lateral sclerosis and frontotemporal dementia - and pointing to a potential target for their therapy.

The authors, working under the guidance of Dr. Chabrel Moussa (Charbel E-H Moussa), found that the problem underlying both diseases is the inability of the intracellular system of neutralization of waste products to remove and destroy excess protein TDP-43 from the nuclei of neurons.

TDP-43 is a nuclear protein that regulates the transcription of thousands of genes. In amyotrophic lateral sclerosis and frontotemporal dementia, the TDP-43 gene is usually mutated or overexpressed. Until now, experts have been of the opinion that inclusions containing the protein product of this gene in the cytoplasm of neurons trigger pathological mechanisms in amyotrophic lateral sclerosis and frontotemporal dementia.

However, the authors found that after removal from the nucleus into the cytoplasm, this protein is destroyed and does not harm cells. At the same time, with excessive production of TDP-43 in the nucleus, the cell cannot cope with the removal of its aggregates into the cytoplasm, and their accumulation in the nucleus leads to neurodegeneration. In amyotrophic lateral sclerosis, this occurs in the motor neurons, which is manifested by impaired motor function, and in frontotemporal dementia - in the neurons of the frontal lobe of the brain, which leads to the development of dementia.

For a long time, Dr. Moussa has been studying the parkin protein, whose dysfunctions are characteristic of familial forms of Parkinson's disease. Based on the results of earlier work, Moussa formulated a hypothesis according to which Parkin can remove toxic fragments of beta-amyloid accumulating in the brain cells of patients with Alzheimer's disease. Moreover, he developed a method of gene therapy, which consists in introducing a gene encoding parkin into the nuclei of neurons. Earlier, in experiments on rodents, this approach has demonstrated effectiveness in removing beta-amylode, which begins to accumulate in the neurons of the brain.

In the framework of the latest work, Moussa and his colleagues demonstrated in two animal models that the described gene therapy approach slows down the progression of amyotrophic lateral sclerosis associated with the accumulation of TDP-43 protein. This is manifested by an improvement in motor functions and an increase in the life expectancy of animals.

According to the authors, Parkin attaches ubiquitin protein molecules to the excess TDP-43 contained in the nucleus – a "black mark" that ensures the removal of damaged or unnecessary proteins into the cytoplasm and destruction. This prevents damage to the nucleus and disruption of gene regulation. In the near future, the researchers plan to check whether the introduction of a drug that stimulates the activity of parkin will have a similar effect.

Article by Michaeline L. Hebron et al. Parkin ubiquitinates Tar-DNA binding protein-43 (TDP-43) and promotes its cytosolic accumulation via interaction with histone deacetylase 6 (HDAC6) published in the Journal of Biological Chemistry.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Georgetown University:
Removing protein 'garbage' in nerve cells may help control 2 neurodegenerative diseases.

26.12.2012