Taking Out the Trash: Molecular Disorder, the Brain, and Ill Health

The field of autism is not alone in reeling from the implications of genetic heterogeneity.  There are over 800 genes linked to autism and it’s still going up. If this many different genes can “cause” autism, it may take us forever to figure out what to do about it.

Neurogeneticists take comfort in the convergence of many of these pathways upon some common brain pathways. But for now this is small comfort to the present generation of affected people, and for at least the next several as well. To find drug targets related to any of these pathways will cost billions of dollars in pharma research, and with drug discovery rates falling we will be spending more and more for less and less results.

There may be a simpler solution much closer at hand.

While most researchers in neurodevelopmental and psychiatric conditions are still hunting for specific molecular and genetic glitches in neurons, in the 2012 Nature paper “Wild-type Microglia Arrest Pathology in a Mouse Model of Rett Syndrome,” Derecki and his colleagues reported that they were able to stop and even reverse the symptoms of a serious genetic disorder of development called Rett syndrome. The mice were given healthy microglial cells through a bone-marrow transplant from wild-type mice (that is, normal healthy mice without the Rett genetic mutation) – and then they got better – and stayed better for at least a year.

This paper is remarkable because it shows that our previous research into Rett syndrome – which primarily addressed dysfunctional neurons – was incomplete. The mice in this study got better because they got new microglia that functioned better. The microglia they’d started with took a hit from the Rett genetic mutation and weren’t doing their job of “taking out the trash” from the neuronal environment. When the healthy microglia came into the system and started doing their job, the disease stopped getting worse and stayed stable – quite unlike the normal course of the condition. When the scientists tested this idea by stopping the “garbage collection” role of the microglia, all the gains were lost and the mice got sicker.

Amazingly, nothing was done to the neuron itself in the intervention. Just the microglia. This suggests that the symptoms of the disorder might be driven by mischief related to the microglia, not just genetic insults to the neurons, as has been assumed. Maybe the problem is the garbage created by the chaos and dysfunction from the gene mutations, not just (or even not mainly) the gene mutation’s impact on the neurons.

So is Rett Syndrome really “neuro”developmental? Or does that term mislead us and put blinders on our vision? Doug Fields, author of THE OTHER BRAIN, a wonderfully readable book on glial cells, suggests as much.

If this is true, is it also possible that conditions like autism, which have also been assumed to be due to neuronal problems, might also be highly shaped by microglial problems? In the case of Rett Syndrome, microglia are messed up for genetic reasons. In lots of other conditions, including autism, microglia may well be activated for some other reason — perhaps just environmental exposure since many exposures and infections can activate microglia. This means that addressing environmental issues – improving food and reducing toxic exposures – may help a lot.

Even in Rett syndrome, where there is certainly a genetic problem, isn’t it possible that more toxic environmental exposures and poor nutrition could make things worse – or vice versa – could healthy environmental inputs improve wellbeing in meaningful ways, slowing the disease’s progression and making people with Rett syndrome less uncomfortable? So often, doctors quit trying to look for ways to help when they find a gene – but even then, perhaps other things can still make life better. More and more parents of children with genetic conditions like Down syndrome are discovering how much better their children can do even though there’s nothing they can do about the gene defect.

Imagine you had the perfect grandparents. You go over to their house and find them trying to get by with one lamp. It is dark and hard to find anything. Checking out the ceiling light, you find that a filament blew. You replace the lightbulb and now you can see. What an immaculate job of housekeeping your grandparents have done. Everything is intact and the only problem was that one lightbulb. How sweet.

Now imagine your grandparents had diabetes, heart failure, and dementia. You come into town to visit after a long time away and you find the lights are dim. When you try to get into their house you find garbage strewn all over the place — they haven’t had the energy to clean up in ages. Old mail, crumpled paper, ripped upholstery, dust. The kitchen is piled with dishes, there is rotten food in the fridge and there are bugs and rodents. Yes you find a few busted lightbulbs, but that is the least of their problems.

The perfect grandparents with the single broken lightbulb are like the dream neurodevelopmental or neuropsychiatric illness. Find the one defect, fix it, and you’re good.

The diabetic, demented grandparents in heart failure are more like the disarray that comes from a combination of mutations and environmental stressors. The mutations create their problems not only by damaging some specific step in a cell, but also by gumming up the works – by causing inefficiency and disconnects in how the cell operates. Proteins don’t fold right, pieces of cellular structures break off, cellular clean-up operations are way behind. What a mess.

To help cells be healthier and to help the brain to function better, there’s a lot we can do without identifying a specific molecule to target with a drug.  If we improve health – through taking care of optimizing food, avoiding toxins and infection, and minimizing stress – as I lay out in my book The Autism Revolution: Whole Body Strategies for Making Life All It Can Be http://www.AutismRevolution.orgmicroglial cells won’t have to work so hard fighting off dangers and may be more effective at everyday housekeeping.

Derecki and his colleagues have since authored a review paper, “The Role of Microglia in Brain Maintenance: Implications for Rett Syndrome,” fleshing out the implications of their finding. These implications may be even greater than they say, since cellular debris may well contribute widely to ill health and neurdegeneration.

Doesn’t it make sense to start testing now to see if the activities we know will improve microglial function will also improve conditions like Rett Syndrome and autism? For many of those whose conditions are more environmental than genetic (which could be a huge number of people), this might make a major difference.

Coda: The typical American diet couldn’t be worse for microglia and the rest of our brain cells, promoting chronic inflammation that traps microglia in a state of “activation” where they spew out all sorts of chemicals, irritating and overexciting the brain.  Maybe the lessons we learn from autism and Rett could help all people function better.

 

An earlier version of this blog appeared on www.autismWHYandHOW.org as Housekeeping and higher functions are married and inseparable in the brain.”

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