The receptor sortilin was found to bind pro-neurotrophins, like proNGF (pro nerve growth factor) and proBDNF (pro brain-derived neurotrophic factor), in dying neurons. Neurotrophins are signaling molecules, secreted by one cell and accepted by another, either in the mature form or in an unprocessed pro-form. The proNGF and proBDNF signal neuronal growth in a developing neuronal system, however, were found to signal neuronal death in mature systems. In previous experiments carried out on rats, the gene encoding for sortilin was found to be highly expressed in neurons that died as a result of an injury. It was then hypothesized that sortilin binds pro-neurotrophins to mediate cell death. This hypothesis was tested using knock-out mice for the gene for sortilin.
The knock-out mice for the gene encoding sortilin showed the behavior predicted by the scientists – they developed normally but showed decreased neuronal death. Using transgenic mice technology, which won its developers the 2007 Noble prize for medicine, the German and Danish researchers created mice with no expression of sortilin. Since sortilin is responsible only for signaling cell death, the mice developed normally. Several tests were then conducted on these mice to show that sortilin indeed signals for cell death. In cell cultures which were taken from the knockout mice and were treated with proNFG and proBDNF, the death rate of neurons was three to four times lower than in the control group mice. Further tests were then performed to determine whether sortilin generates cell death in different situations.
The research demonstrated that the knockout mice’s neurons managed to evade death, usually related to injury and aging. Comparing a certain type of neurons, the researchers observed that after 60 weeks, 45% of the neurons were dead in the control group mice, while 100% of the neurons stayed alive in the sortilin-free knockout mice. In the experiments conducted in order to determine the role of sortilin in the case of an injury, it was observed that about 95% of the cells in the knockout mice survived in the injured area as opposed to only 60% surviving neurons in the control group mice. Scientists now believe that sortilin has a major role in signaling neuronal cells death in various death pathways.
The research points out the role of one receptor in the signaling cascade of cell death. The findings indicate th receptor is probably a major component in the death process, as its deletion significantly decreases cell death rates. On the basis of this discovery, is may be possible to develop medicines that reduce the number of cells negatively affected by injuries or strokes and to help treat neuronal disorders related to premature cell death, such as Alzheimer’s disease.