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motor neurons

‘Matchmaker’ role for protein behind SMA

Motor neurons connect the spinal cord to the muscles. They can be a meter long in adult humans. SMA (spinal muscular atrophy) affects approximately 1 in 10,000 babies. It impairs the ability to move and breathe, and in its most severe form, kills before the age of two.

A puzzling question has lurked behind SMA (spinal muscular atrophy), the leading genetic cause of death in infants.

The disorder leads to reduced levels of the SMN (survival of motor neurons) protein, which is thought to be involved in processing RNA, something that occurs in every cell in the body. So why does interfering with a process that happens everywhere affect motor neurons first?

Scientists at Emory University School of Medicine have been building a case for an answer. It’s because motor neurons have long axons. And RNA must be transported to the end of the axons for motor neurons to survive and keep us moving, eating and breathing.

Now the Emory researchers have a detailed picture for what they think the SMN protein is doing, and how its deficiency causes problems in SMA patients’ cells. The findings are published in Cell Reports.

Wilfried Rossoll, PhD in the lab.

“Our model explains the specificity — why motor neurons are so vulnerable to reductions in SMN,” says Wilfried Rossoll, PhD, assistant professor of cell biology at Emory University School of Medicine [and soon moving to the Mayo Clinic in Jacksonville]. “What’s new is that we have a mechanism.”

Rossoll and his colleagues showed that the SMN protein is acting like a “matchmaker” for messenger RNA that needs partners to transport it into the cell axon.

RNA carries messages from DNA, huddled in the nucleus, to the rest of the cell so that proteins can be produced locally. But RNA can’t do that on its own, Rossoll says. In the paper, the scientists call SMN a “molecular chaperone.” That means SMN helps RNA hook up with processing and transport proteins, but doesn’t stay attached once the connections are made.

“It loads the truck, but it’s not on the truck,” Rossoll says. [Read the rest of Emory’s press release here.]

He also tells me that even though the two diseases affect very different age groups, SMA and ALS (amyotrophic lateral sclerosis) have two things in common: they both affect motor neurons and they both involve proteins that transport RNA. He says an emerging idea in the field is that SMA represents a problem of “hypo-assembly” while ALS is a problem of “hyper-assembly.”

Posted on by Quinn Eastman in Neuro Leave a comment

Happy birthday, spinal cord neurons

Congratulations to JoAnna Anderson, postdoctoral fellow in Francisco Alvarez’ lab, for winning the Best Image contest, part of the Postdoctoral Research Symposium taking place Thursday. We will have explanations of the second and third place images Thursday and Friday.

The brief description of Anderson’s image is: “EdU birthdating of V1 inhibitory interneurons in the postnatal day 5 lumbar spinal cord.” But how did all those colors get in there and what do they mean? Alvarez explains:

The work is about finding the times of neurogenesis of the many inhibitory neurons that pattern motor output in the ventral horn of the spinal cord, so that our muscles contract in a coordinated manner to achieve the desired movements.

For example, when one muscle contracts, the muscle with the opposite action on the same joint will be inhibited. Anderson and her fellow postdoc Andre Rivard have been studying the development of the V1 neurons that carry out this inhibition.

AndersonJoAnnaThe image shows a slice of a 5 day old mouse’s spinal cord, and we can see individual cells. Some of the neurons are producing fluorescent proteins: one of the proteins is red, the other is green, and where both proteins are present, a yellow or orange color can be seen. The red and the green colors are indicators for two genes, Engrailed-1 and FoxP2, respectively, both of which regulate neurons’ development.

In addition, the white spots at the top come from EdU (5-ethynyl-2’-deoxyuridine), a chemical that impersonates a building block of DNA well enough to get incorporated into cells when they are dividing. It is helpful to remember that neurons are cells that have stopped dividing. Giving embryos a pulse of EdU is a way to mark the point at which progenitor cells mature and become neurons.

By repeating the experiment at different dates, the researchers can see that FoxP2 positive green cells are generated after the FoxP2 negative red cells. Both types of cells are derived from the same progenitors, but in different cell cycles. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Rethinking the role of an aggregation-prone protein in ALS

Anyone studying neuroscience will notice that many neurodegenerative diseases seem to have their own sticky, possibly toxic protein. This protein tends to aggregate, or clump together, in or near the cells affected by the disease.

Picture a glass of milk left in a warm place for several days. Yuck. That is the macro version of the microscopic clumps scientists believe are bothering the brain. For many diseases, there is a debate: are the clumps by themselves toxic to neurons, or a byproduct of something else killing the cells?

Parkinson’s disease has one of the pesky proteins: alpha-synuclein. Alzheimer’s disease has two: beta-amyloid outside cells and tau inside. ALS (amyotrophic lateral sclerosis) has at least three.*

One of them, TDP-43, is found in protein aggregates in most forms of ALS, both familial and sporadic. Mutations in the TDP-43 gene also account for a small fraction of both familial and sporadic forms of ALS. This suggests that even the normal protein can create problems, but a mutated version can accelerate the disease. In addition, TDP-43 aggregates have been connected with other diseases such as frontotemporal dementia.

Again, it’s not clear whether the aggregates themselves are toxic, or whether it’s more a matter of TDP-43, which appears to regulate RNA processing, is not doing what it’s supposed to in the cell.

TDP-43 protein is mobile within motor neurons.

Emory cell biologists Claudia Fallini and Wilfried Rossoll have been probing the effects of tweaking TDP-43 levels in motor neurons, the cell type vulnerable to degeneration in ALS. They find that motor neurons may be more sensitive to changes in TDP-43 levels than other neurons, which may explain why ALS selectively affects motor neurons.

The results were published in Human Molecular Genetics.

Fallini was able to obtain a movie of fluorescently-tagged TDP-43 “granules” moving around in live motor neurons. Importantly: this is healthy/functional, not aggregated/ toxic protein. The finding that TDP-43 is mobile implies that it has something to do with transporting RNAs around the cell, rather than only functioning in the nucleus.

“Our data point to the hypothesis that TDP-43 increased localization in the cytoplasm is the early trigger of toxicity, followed by protein aggregation,” Fallini says. “Because motor neurons are unique neurons due to their high degree of polarization, we believe they might be more sensitive to alterations in TDP-43 functions in the cytoplasm or the axon.”

In particular, the researchers found that elevated levels of TDP-43 provoke motor neurons to shut down axon outgrowth. They focused on a role for the C-terminal end of TDP-43 in this effect.

“Nobody had looked at TDP-43 specifically in motor neurons before,” she says. “Our paper for the first time shows the localization and axonal transport of TDP-43, and the effects of TDP-43 altered levels on motor neuron morphology.”

*Another ALS protein, SOD1 (superoxide dismutase), apparently forms toxic aggregates when mutated in some cases of familial ALS. At Emory, Terrell Brotherton and Jonathan Glass have been investigating these forms of SOD. The third protein, FUS, has similar properties to TDP-43.

 

Posted on by Quinn Eastman in Neuro Leave a comment