Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is the most common form of motor neuron disease. People with ALS gradually lose the ability to initiate and control muscle movements, including the ability to speak, swallow, and breathe.
There is no known cure. But recently, we studied mice and identified a new target in the fight against this devastating disease: the brain’s waste disposal system.
Neurodegenerative Diseases – including Parkinson’s, Alzheimer’s and multiple sclerosis – have many similarities, even though their clinical signs and disease progression may look very different. The incidence of these diseases increases with age. They are progressive and relentless, resulting in a gradual loss of brain tissue. We also see waste proteins accumulating in the brain.
Our new study looked at how the glymphatic system, which clears waste products from the brain, might prevent ALS.
Protein chains, folds and misfolds
In our bodies, long protein chains fold to form functional shapes that enable them to perform specific tasks such as making antibodies to fight infections, supporting cells or transporting molecules.
Sometimes this process goes awry, resulting in “misfolded” proteins that clump together to form aggregates. Misfolded protein can grow and fragment, creating seeds that spread throughout the brain to form new clusters.
The accumulation of waste proteins begins early in the neurodegenerative disease process – well before the onset of symptoms and brain loss. As researchers, we wanted to see if eliminating or slowing the spread of these waste proteins and their seeds could stop or slow the progression of disease.
Target Waste Disposal
The glymphatic system removes waste products, including toxic proteins, from the brain.
This brain-wide network of fluid-filled spaces, known as Virchow-Robin spaces, usually turns off when we are awake. But it switches on during sleep to disperse compounds essential for brain function and to get rid of toxic waste.
This may explain why all beingsbig and small (even fly), needs sleep to survive. (Interestingly, whales and dolphins alternate their sleep between hemispheres, keeping the other hemisphere awake to watch for predators and warning them to breathe!)
As we age, sleep quality refuses and the risk of neurodegenerative diseases, including ALS, is increasing.
Sleep disturbances are also a common symptom of ALS, and research has shown that a single night of no sleep can lead to: increased accumulation of toxic waste protein in the brain. As such, we thought that glymphatic function might be impaired in ALS.
To investigate this, we looked at mice. The animals were genetically engineered to express human TDP-43 – the protein involved in ALS. By feeding these mice food containing an antibiotic (doxycycline), we were able to knock out TDP-43 protein expression and they became normal. But when the mice are switched to normal food, TDP-43 expression is turned on and misfolded proteins begin to accumulate.
Over time, the mice show the classic signs of ALS, including progressive muscle dysfunction and brain atrophy.
Using magnetic resonance imaging (MRI) to see brain structure, we examined glymphatic function in these mice just three weeks after turning on TDP-43 expression.
As we watched the glymphatic system go to work, we saw that the TDP-43 mice had poorer glymphatic clearance than the control mice that were not genetically modified. Importantly, these differences were seen very early in the disease process.
Our study provides the first evidence that the glymphatic system may be a potential therapeutic target in the treatment of ALS.
How can we improve glymphatic function?
Not all sleep is created equal. Sleep includes both rapid eye movements (REM) and non-REM sleep. This last stage includes slow wave sleep – when the glymphatic system is most active† Sleep therapies that enhance this phase may prove particularly beneficial for preventing diseases such as ALS.
Sleeping position is also thought to influence glymphatic clearance.
Research in rodents has demonstrated glymphatic clearance is most efficient in the lateral (or side-sleeping) position, compared to supine (on the back) or prone (facing forward). The reasons for this are not yet fully understood, but may have to do with the effects of gravity, compression and stretching of tissue.
Lifestyle choices can also be helpful in improving glymphatic function. Omega-3, found in marine fish, has long been considered beneficial for health and reduces the risk of neurodegenerative diseases. New research shows these benefits may be due in part to the positive effect of: Omega-3 on glymphatic function†
Moderate consumption of alcohol has been shown to improve waste clearance. In mouse studies, both short-term and long-term exposure to small amounts of alcohol have been shown to stimulate glymphatic function while high doses had the opposite effect.
Excercise has also proved beneficial.
All of these studies show that small lifestyle changes can improve brain waste clearance to minimize the risk of neurodegenerative diseases. Next, research should focus on therapies that target the glymphatic system directly to help those already suffering from these debilitating diseases.
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