View on Causal Mechanism in ALS

Photo: Microscopic image of a spinal cord section

This is a microscopic image of a
spinal cord section, in which
energy-producing organelles
(mitochondria) were labeled
using a fluorescent protein
derived from jellyfish. The nuclei
of cells are labled in magenta;
© TUM

One of the ways neurodegenerative diseases manifest themselves is in the loss of axons – essentially, the transmission lines for electrical signals in individual nerve cells – and synapses, the key sites for communication between them. In the past, such damage has been attributed to deficits in the bidirectional transport of organelles, such as the intracellular power plants called mitochondria, along the axons of nerve cells. Now, researchers at the Technische Universitaet Muenchen (TUM) and Ludwig-Maximilians-Universitaet Muenchen (LMU) have put that assumption under the microscope in the most thorough test to date. They used novel imaging techniques to observe changes in both axon morphology and organelle transport – with high resolution in both space and time – in several different animal models of ALS. Their results show that transport deficits and axon degeneration can develop independently, refuting the hypothesis that one is a direct cause of the other.

The lead researchers in this study were Professor Thomas Misgeld of the TUM Institute of Neuroscience, a Fellow of the TUM Institute for Advanced Study, and Professor Martin Kerschensteiner of the LMU Institute of Clinical Neuroimmunology. Together with Misgeld's research group, they observed axonal organelle transport in living tissue in real time – and in a way that enabled them to track the movement of individual mitochondria – using a novel imaging approach that involves transgenic labeling. They were also able to observe transport of another kind of organelle, endosome-derived vesicles. Several different animal models of ALS were investigated, all of which are based on human mutations associated with the disease.

The researchers investigated a number of different questions arising from this surprising result, using multiple animal models of ALS and focusing on motor neurons, the kind of neuron most affected in this disease. By comparison, most previous studies of the putative link between organelle transport and ALS had been limited: Some, for example, focused on a single mutation, made their observations in vitro or in non-motor nerve cells, or did not include a wild-type mutation as a control. Others measured surrogates for organelle transport deficits instead of observing transport directly.

Among the conclusions: In ALS models, reduction of organelle transport and initiation of axon degeneration appear to be due to different mechanisms. This suggests that, at least for ALS, axonal organelle transport may be an unsuitable therapeutic target.

MEDICA.de; Source: Technische Universitaet Muenchen