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Researchers find another piece in Alzheimer’s puzzle

12.11.2013
The protein spastin cuts off supply lines inside nerve cells

A team of German and American researchers has added another piece to the puzzle of what causes Alzheimer disease. They have found that a protein called “spastin” plays a previously unsuspected role: spastin is able to cut off the supply lines inside nerve cells, causing their death.

Therefore, substances which specifically inhibit this protein could have a positive effect on the progress of the disease.

Scientists at the Bonn site of the German Center for Neurodegenerative Diseases (DZNE), the caesar research center and the Hamburg Outstation of the Max Planck Institute for Neurological Research took the lead in these investigations. The study was published in the EMBO Journal.

Alzheimer disease causes the memory to fade, ending with complete disorientation and dementia. It also triggers the death of vast quantities of nerve cells in the brain. At present, the causes of Alzheimer’s are only partly understood. The disease is said to be “multifactorial”. Researchers in Bonn, Hamburg and the US have now identified another protagonist called “spastin”. This protein is not new to the field of neurodegenerative diseases. Pathological changes to this protein are considered to be the main cause of hereditary spastic paraplegia. “Mutated spastin damages the cells in the spinal medulla, causing paralysis of the legs. We have now found that spastin, in this case its healthy form, can damage brain cells if not controlled properly. This was a surprise, because Alzheimer research has paid only scant attention to spastin so far,” says neuroscientist Eva-Maria Mandelkow. She is a researcher on Alzheimer disease and cooperates closely with her husband Eckhard Mandelkow. The couple runs labs both in Bonn and Hamburg.

During experiments with cell cultures, the Mandelkow team – including first author Hans Zempel, who is a PhD student at the DZNE in Bonn – found that spastin can damage the supply lines inside the dendrites. Dendrites are fine ramifications of the cell body by which the nerve cell receives stimuli from other cells. But cellular contacts wither if substances important for the cell’s metabolism are not transported properly. If the supply lines – known as microtubules – are severed, the dendrites and ultimately also the nerve cells will perish. The researchers also observed this reaction in their laboratory experiments.

A fatal chain reaction

It is known that the number of microtubules in the nerve cells diminish in cases of Alzheimer disease. This affects not only the delicate dendrites but also the axon, a long cell extension by which the nerve cell transmits signals. “The factors which cause the decline of the microtubules do not necessarily appear to be the same for dendrites and axons,” remarks Eva-Maria Mandelkow. “Our investigations are now creating a clearer picture of why the microtubules in the dendrites disappear. We have been able to prove that the effect of spastin is part of a chain reaction which involves the proteins A-Beta and Tau, among others.”

A-Beta and Tau have long been held responsible for brain pathology in Alzheimer disease. These proteins are normally isolated, but in cases of Alzheimer they become sticky and form protein clumps that appear as the typical “plaques” and “tangles” in Alzheimer brains.

The scientists treated nerve cells with aggregates of the protein A-Beta, thus triggering a sequence of events. Most specifically, the cells now lost control over the proper distribution of Tau proteins, which accumulated in the dendrites. This brought about a chemical change in the microtubules there. “The microtubules became more susceptible to spastin. The protein has the effect of molecular scissors which cut the microtubules into pieces,” says the neuroscientist.

In the healthy organism, this function is strictly regulated. In itself, it is nothing special, because microtubules are constantly broken down and replaced by new ones. However, in Alzheimer disease, this breakdown process gets out of control. “The natural effect of spastin is enhanced. As a result, the microtubules are chopped to pieces,” says Eva-Maria Mandelkow.

Therapeutic potential

In a commentary in the EMBO Journal, US researchers Daphney Jean and Peter Baas, who were not involved in the current study, speculate that some of the experimental substances against Alzheimer could reinforce the negative effect of spastin. They note that at present, substances are being tested which improve the cohesion of the microtubules, but this may not hinder the scissor effect of spastin. Rather the opposite. This is due to the structure of the elongated microtubules, which are naturally made up of stable and comparatively unstable segments. Stabilizing substances cause the unstable segments to shrink while the stable segments grow. Such microtubules provide a greater contact area for spastin. This is because the protein prefers to cut through the stable segments of the microtubules.

A suitable therapeutic approach could be to specifically inhibit the effect of spastin. “Our results indicate that substances which block spastin may have a positive effect on the progress of Alzheimer. However, we have to be careful with prognoses,” says Eva-Maria Mandelkow. “Alzheimer is a disease with many facets and picking just one is unlikely to be enough. However, the important point is that we have identified a puzzle piece which will help us understand the disease better.”

Original publication
“Amyloid-ß oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin”, Hans Zempel, Julia Luedtke, Yatender Kumar, Jacek Biernat, Hana Dawson, Eckhard Mandelkow, Eva-Maria Mandelkow, The EMBO Journal, online publication dated September 24, 2013, http://dx.doi.org/10.1038/emboj.2013.207
Commentary (“Have you seen?”)
“It cuts two ways: microtubule loss during Alzheimer disease”, Daphney C. Jean, Peter W. Baas, The EMBO Journal, online publication dated September 27, 2013, http://dx.doi.org/doi:10.1038/emboj.2013.219

Dr. Marcus Neitzert | idw
Further information:
http://www.dzne.de

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