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In science, refuting a hypothesis can be as significant as provingone, all the more so in research aimed at elucidating how diseasesproceed with a view toward preventing, treating, or curing them.Such a discovery can save scientists from spending precious yearsof effort exploring a dead end. In a study published in the Proceedings of the National Academy of Sciences , Munich-based researchers refute a widely accepted hypothesisabout a causative step in neurodegenerative conditions. Theseresults deal specifically with animal models of human amyotrophic lateral sclerosis (ALS, aka Lou Gehrig's disease ) but also raise questions for research on other neurodegenerativediseases, such as Alzheimer's or Huntington's disease . One of the ways neurodegenerative diseases manifest themselves isin the loss of axons - essentially, the transmission lines forelectrical signals in individual nerve cells - and synapses, thekey sites for communication between them. In the past, such damagehas been attributed to deficits in the bidirectional transport oforganelles, such as the intracellular power plants calledmitochondria, along the axons of nerve cells. Now, researchers atthe Technische Universitaet Muenchen (TUM) andLudwig-Maximilians-Universitaet Muenchen (LMU) have put thatassumption under the microscope in the most thorough test to date.They used novel imaging techniques to observe changes in both axonmorphology and organelle transport - with high resolution in bothspace and time - in several different animal models of ALS. Theirresults show that transport deficits and axon degeneration candevelop independently, refuting the hypothesis that one is a directcause of the other. The lead researchers in this study were Prof. Thomas Misgeld of theTUM Institute of Neuroscience, a Fellow of the TUM Institute forAdvanced Study, and Prof. Martin Kerschensteiner of the LMUInstitute of Clinical Neuroimmunology. Together with Misgeld'sresearch group, they observed axonal organelle transport in livingtissue in real time - and in a way that enabled them to track themovement of individual mitochondria - using a novel imagingapproach that involves transgenic labeling. They were also able toobserve transport of another kind of organelle, endosome-derivedvesicles. Several different animal models of ALS were investigated,all of which are based on human mutations associated with thedisease. "The methods - both in terms of labeling and in terms of livemicroscopy - that Martin Kerschensteiner and I have developed overthe past years to track mitochondria in intact axons now allowedour student, Petar Marinkovi , to look directly into models ofALS," Misgeld explained. "The result came a bit as a surprise, aswe fully expected a problem with transport of these organelleswould be present in all the disease models and missing in all thecontrols. Well, the results taught us differently." The researchers investigated a number of different questionsarising from this surprising result, using multiple animal modelsof ALS and focusing on motor neurons, the kind of neuron mostaffected in this disease. By comparison, most previous studies ofthe putative link between organelle transport and ALS had beenlimited: Some, for example, focused on a single mutation, madetheir observations in vitro or in non-motor nerve cells, or did notinclude a wild-type mutation as a control; others measuredsurrogates for organelle transport deficits instead of observingtransport directly. Among the conclusions: In ALS models, reduction of organelletransport and initiation of axon degeneration appear to be due todifferent mechanisms. This suggests that, at least for ALS, axonalorganelle transport may be an unsuitable therapeutic target. In addition, Misgeld said, "We do think these insights haveimplications for other studies of ALS, or even studies of otherneurodegenerative diseases. What our experiments really say is thatit is not easy to develop faithful models of neurodegenerativediseases. So it might be worth spending more effort to get betteranimal models, as this is the only way forward for mechanisticstudies, while always checking them against human pathology orhuman-derived cellular models. In the meantime, it is probablyprudent to work with several of the available models in parallel.Moreover, in more general biological terms, our results also speakto the relationship between axonal transport disruptions anddegeneration - which might not be as tight as we assumed. Here wehave a lot more to understand." Additional References Citations. The e-commerce company in China offers quality products such as Vacuum Slimming Machine Manufacturer , E-light IPL RF, and more. For more , please visit Ultrasound Cavitation Slimming Machine today!
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