ALS Target: Microglia

Glia, perhaps the most underappreciated of cell types, are finally getting some attention. A new report in Science Translational Medicine from Kevin Eggan’s group at the Harvard Stem Cell Institute validates the role of microglia in amyotrophic lateral sclerosis – aka ALS, motor neuron disease or Lou Gehrig’s disease — and investigates how to manipulate them to extend life, in a mouse model for now.

NOT JUST BYSTANDERS
Often described as inert scaffolding, bystanders, or background cells, neuroglial cells – glia for short– actually do quite a lot. In the central nervous system, the several types -– astrocytes, oligodendrocytes, ependymal cells, and microglia — provide nutrients and growth factors, mop up excess neurotransmitters from synapses, form the intricate architecture that supports axons, provide insulating myelin, and control the communications of neurons.

The relative numbers of neurons and glia have long been a matter of debate, but consensus seems to be emerging of a near 1:1 ratio. And because neurons don’t divide and glia do, there’s a lot of life and death among the so-called bystanders. Not surprisingly, when brain tumors form, they’re typically glial. Neurons must revert to a more plastic developmental state to veer onto a pathway towards cancer.

When I began coauthoring a human anatomy and physiology textbook years ago, one of the first things I did was to redo the glia section, freeing them from their stereotyped supportive roles and giving them proper respect.

All specialized cells derive from pathways that branch from stem cells. Most glia are cousins of sorts to neurons, descending from division of the same neural progenitor cells. Yet some microglia come from hematopoietic stem cells, the “mother” cells of the bone marrow. Brain cells coming from the bone marrow makes it possible to treat some brain diseases with bone marrow transplant, such as adrenoleukodystrophy. Clinicaltrials.gov lists a few such efforts for ALS.

Microglia mediate signaling of prostanoids, which include the prostaglandins, hormone-like fatty acids that control inflammation, among other activities. In the brain microglia aggregate near damage, but in ALS, overactive versions of the cells might contribute to the pathology. PET scans show supercharged microglia in the brains of ALS patients, and heightened signaling in their spinal fluid.

Dr. Eggan and colleagues called attention to the possible role of microglia in ALS in 2008. “Now 6 years later, after considerable effort and many long-term experiments, we’ve been able to better pinpoint the source of those signals in the nervous system in an animal model, as well as show that the prediction we made using a stem cell model of disease can hold up to closer scrutiny in the context of a whole animal,” Dr. Eggan said in a news conference yesterday. The research trajectory is in a sense circuitous, demonstrating mechanisms in human cells that are then repeated in mice, to collect evidence to catalyze clinical trials of compounds that intervene in the pathological process.

STEM CELLS ARE CRITICAL FOR STUDYING NEURONS

Using human embryonic stem (hES) cells or induced pluripotent stem (iPS) cells is particularly important in studying diseases of the nervous system because neurons don’t divide. Otherwise where would new ones come from in a culture dish?

Contrary to the popular but deficient definition of stem cells as “cells that can turn into any cell type,” the defining characteristic is ability to self-renew – make another stem cell. If stem cells magically “turned into any cell type in the body,” there would quickly be nothing left to keep things going.

A stem cell can self-renew and generate a neural progenitor cell that in turn can divide to give rise to neurons and glia. The Eggan team first created iPS cells from an ALS patient  in 2008.

Microglia apparently harm motor neurons via a specific type of overactive prostanoid receptor. First author and grad student Sophie De Boer and her colleagues at HSCI, Massachusetts General Hospital, and Boston Children’s Hospital, conducted a brilliant series of experiments that show that blocking or removing the errant receptors may be one route to extending survival in ALS.

ELEGANT EXPERIMENTS

In the new study, the investigators exposed human motor neurons derived from ES cells and marked with green fluorescent protein (GFP) to sheets of “toxic” glia from mice that have a form of ALS due to mutation in the superoxide dismutase 1 (SOD1) gene. At last count, 7 human genes had been implicated in the 5 to 10% of cases that are inherited; SOD1 was the first and is the best studied.

The SOD1 toxic microglia killed more than half of the neurons, but chemically blocking the receptors enabled the neurons to survive.

In complementary experiments, activating receptors in normal glia turned them toxic – but only to motor neurons, and not other neuron types. Removing the gene encoding the protein that forms the receptor had the same effect as blocking it chemically. And perhaps most important in a translational medicine sense, a short blast of antagonist had a long-lasting effect on the health of the motor neurons. Plus the effect is seen in actual living animals, increasing lifespan in mice.

The most exciting part of the new work is that it zeroes in on a “druggable” target – the DP1 receptor and its associated signalling pathways. The receptor is a G protein, a membrane-spanning molecule that is already the basis of many drugs. Said Dr. Eggan, “At least two major pharmaceutical companies have significant development programs around this receptor for another indication — niacin induced flushing.” Perhaps these candidate drugs can be retasked to inhibit inflammatory effects in ALS, he added, and possibly teamed with a seizure medication the researchers identified earlier this year that fights ALS by a different route.

WHAT CAUSES ALS?
ALS is like Alzheimer and Parkinson diseases in that a shared phenotype might represent any number of different gene-environment interactions. What’s true for an individual with SOD1 ALS may not be so for a person with a different mutant gene.

The ALS patient I posted about in April, Glenn, didn’t have any known mutations, but he did have a few environmental risk factors. He played football for many years, maybe getting clunked in the head one too many times, and may have been exposed to pesticides when his boyhood home (to which he moved back as an adult) bordered fields of crops. Smoking, aspartame, and exposure to formaldehyde and heavy metals are other suspects. Reports that vitamin E protects against ALS haven’t held up.

Perhaps the most fascinating causal candidate is exposure to cyanobacteria (aka blue-green algae) living in cycad trees on Guam. The cyanobacteria release an amino acid called BMAA into the soil, where it makes its way through the roots to the seeds of the cycads. After biomagnification through food webs, BMAA causes an ALS-like disease when it binds proteins in the brains of some individuals, who may be genetically-predisposed to the motor neuron damage.

STEM CELLS FIND THEIR NICHE

Do people survive ALS? The disease may be so heterogeneous that this might be possible. One commentator on my previous ALS post took me to task for not mentioning this idea, which I admit I was not aware of, but I found his tone disturbing. He wrote:

“C’mon, time to wake up and smell the coffee. People have been solving ALS for years, and the only way to really do it is change diet, psychology and lifestyle.”

He linked to a website offering accounts of recoveries, and then commented on Dr. Eggan’s team’s identification of the seizure drug for possible repurposing:

“While maybe that drug will be of some use somehow, don’t let that distract you from the overall reality of the situation. Stem cells? Eh, just learn to heal.”

I don’t think the commentator intended to upset ALS patients who haven’t managed to heal themselves, and I understand the value of hope. But an anti-science stance certainly isn’t going to help. I’m reminded of Captain Picard on Star Trek: Next Generation saying “make it so,” or the professor in The Music Man teaching kids to play instruments using the “think” system rather than learning music theory.

Positive thoughts aren’t enough.

Using stem cells to recapitulate the precise choreography of a disease, illuminating the various drug targets and their interactions, and then deploying drugs old and new based on those discoveries, may indeed “make it so,” slowing, vanquishing, and ultimately preventing this heartbreaking and complex disease.

I think that use of stem cells to create “diseases-in-a-dish” will turn out to be their most successful application. The very quality of self-renewal that many news reports omit is what scares me. Stem cells used therapeutically that self-renew, perhaps in places unexpected, could form a tumor.

Coincidentally, I just received an e-mail from Maurie Hill, whose participation in a clinical trial to treat Stargardt disease, a form of visual loss, was the subject of the very first DNA Science post, Human Embryonic Stem Cells Finally Reach Clinical Trials: Maurie’s Story, nearly two years ago. Alas, her vision has not improved at all, although I do not know the findings of the frequent tests she undergoes — just that she’s very disappointed.

But use of stem cells wedded to drug discovery? That’s a can’t-miss! Congrats Eggan lab for the continuing fine work.