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Of Mice and Flies: A Cutting-Edge Method for Detecting Neurodegenerative Disease Targets

For release: Thursday, May 16, 2013

Fly ‘Nose’ Neurons Help Sniff Out Proteins Suspected of Regulating Neurodegeneration.
Fly ‘Nose’ Neurons Help Sniff Out Proteins Suspected of Regulating Neurodegeneration. In this image green, stringy fly olfactory receptor neuron (ORN) axons project from antennae (not shown) on either side of a fly head to bulbous antennal lobes in the brain (top). The antenna from the right-hand, injured side of the fly’s head was removed. Normally, this would cause the axons to completely degenerate and disappear. Genetically removing a protein called ROCK2 from this fly’s ORNs slowed degeneration, suggesting it is a new target for disease treatments. Courtesy of Freeman Lab University of Mass. Medical School, Worcester.

Studying neurodegenerative diseases can be like investigating a crime.  Scientists inspect damaged nervous tissue, or "the scene", for suspicious molecules and then work backwards to explain how the suspects may have killed nerve cells.  Recently two research groups, one in the United States and the other in the United Kingdom, collaborated to develop a new way to quickly round up many more suspects and test their "alibis".  Their results may lead to more effective treatments for Alzheimer's disease, Parkinson's disease and a variety of other neurodegenerative disorders.

"Every time you find a new molecule involved in degeneration that’s a new target," said Marc R. Freeman, Ph.D, an associate professor in the Department of Neurobiology at the University of Massachusetts Medical School, Worcester.

Recently Dr. Freeman and his colleagues published a study in PLOS Genetics in which they combined an advanced research method called proteomics with studies of flies to find five new suspect molecules.  The approach may change the way researchers search for targets and the results support a new way of thinking about the causes of neurodegenerative diseases.

Scientists have long thought that neurodegenerative diseases initially destroy the main, central body of nerve cells, or neurons.  However, recent studies increasingly suggest that the initial damage begins out in the extremities of a neuron with the destruction of axons, which are long stringy structures.  Neurons typically use axons to send signals to other neurons at communication points, called synapses. 

"The hope is that if you can identify the molecules that control axon degeneration then you can find ways to keep neurons healthy," said Dr. Freeman.

Dr. Freeman’s lab uses a type of fly, called Drosophila melanogaster, to study axons.  He worked with a lab in the UK to search for molecules that regulate axon damage during neurodegeneration.  The UK group was led by Thomas H. Gillingwater, Ph.D., a professor of neuroanatomy at the University of Edinburgh’s Centre for Integrative Physiology and Euan MacDonald Centre for Motor Neurone Disease Research.

Dr. Gillingwater's lab uses the latest in proteomics to study neurodegenerative diseases.  Proteomics is a term that describes large-scale, automated methods for studying molecules called proteins.  Before proteomics, scientists had to perform multiple experiments while searching for a few disease-related proteins at one time; now they can identify many suspect proteins in one experiment.

The researchers used proteomics to study changes in axon and synapse protein levels that occur in three mouse models of neurodegeneration.  In the first model they induced degeneration in a part of the brain called the striatum. 

Initially the researchers found the levels of hundreds of proteins changed, some increased whereas others decreased.  Further experiments suggested that degeneration appeared to greatly change the levels of at least forty seven proteins that are known to be important for axon growth and neuronal communication.  Previous studies implicated many of these same proteins in several neurological disorders, supporting the idea that proteomics can quickly "round-up" a range of suspect molecules.

Next the researchers measured the levels of eleven of the forty seven suspect proteins in mouse models of Huntington’s disease and Spinocerebellar Ataxia.  At least six proteins changed in the same pattern seen during the initial experiments, with the levels of three increasing and three decreasing.  The results suggest these molecules commonly regulate degeneration in multiple disorders. 

Finally, the researchers tested their suspects’ alibis by removing fly antennae.  Flies use their antennae to smell.  As with human noses, fly antennae contain neurons that detect odors, called olfactory receptor neurons (ORNs).  ORNs send odor signals along axons to a structure in the fly brain called the antennal lobe where they communicate with other neurons.  Removing an antenna causes ORN axons to degrade and quickly disconnect from the antennal lobe.

The researchers tested the role of suspect proteins in degeneration by genetically eliminating each one from a fly's ORN neurons.  Eliminating two proteins, called ALDHA1 and Auxillin/DNAJC6, caused the axons to spontaneously degenerate, suggesting their presence helps keep axons healthy.  In contrast, eliminating four other proteins, CALB2/calretinin, CSP/DNAJC5, HIBCH, and ROCK2, delayed degeneration after antennae were removed (see figure). 

Flies and mice are very different animals.  Nonetheless, by combining proteomics with genetics, Dr. Freeman and his colleagues quickly identified at least five suspect proteins that may be important for axon health in both animals.  The results suggest the new suspects regulate axon health in all animals, as well as humans.  This approach may hasten the search for treatment targets of multiple neurodegenerative diseases.

"This is a good first step. Ultimately we want to discover the molecules that have been involved with degeneration throughout evolution," said Dr. Freeman.

- By Christopher G. Thomas, Ph.D.

Reference: Wishart et al., "Combining Comparative Proteomics and Molecular Genetics Uncovers Regulators of Synaptic and Axonal Stability and Degeneration In Vivo." PLOS Genetics, August 30, 2012, Vol. 8(8), pp. e1002936. DOI: 10.1371/journal.pgen.1002936

Last Modified May 22, 2013