New Hope for Parkinson’s Patients

Tantalizing new studies point to a potential treatment.

Posted Jun 24, 2020

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Replacing the missing pieces in Parkinson's.
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Parkinson’s is a remorseless, incurable disease that causes stiffness, tremors, difficulty walking, and depression. People suffering from the disease have a loss of nerve cells (neurons) in an area of the mid-brain called the substantia nigra. Latin names always sound impressive, but this one just means “black stuff." When you dissect it, the substantia nigra looks like an ink stain — unless there’s Parkinson’s, and then it’s as pale as the surrounding tissue. That’s due to the loss of neurons that produce dopamine. As a consequence of this die-off, Parkinson’s patients have a deficit of dopamine in the mid-brain.

Jacking up levels of dopamine can help, but — like most neurotransmitters — dopamine can’t cross the blood-brain barrier. That means that you can’t simply pop a dopamine pill. Instead, in the 1960s, Arvid Carlsson found that a precursor to dopamine, called L-dopa, could cross the blood-brain barrier and help with symptoms of Parkinson’s. It’s not a perfect drug. The stereotypical motions of many Parkinson’s patients, called dyskinesia, are due to L-dopa, not the disease. It is difficult to properly calibrate the dosage, and patients often teeter between catatonia and dyskinesia.

Origin Stories

That’s why three recent studies are so heartening. The first is from Haydeh Payami and colleagues at the University of Alabama, who found a gut-microbial signature that is associated with Parkinson’s. They were guided in their research by a well-known connection between Parkinson’s and the gut, including constipation, inflammation, and “leaky gut." The latter is a contentious term, because the gut is leaky by design: That’s how nutrients are absorbed. But taken to extremes, that leakiness may allow bacteria and toxins to enter the bloodstream, where they are dutifully pumped by the heart to every organ in the body. The immune system destroys these wayward microbes and then stands down. But if it is constantly stimulated, it can lead to chronic systemic inflammation, which can affect the blood-brain barrier and thus, the brain.

Studies consistently show that the gut microbes of Parkinson’s patients are significantly altered from normal. They have higher levels of pathogenic bacteria and lower levels of beneficial bacteria — a double threat. Among the bad bacteria are the opportunistic pathogens Corynebacteria, Porphyromonas, and Prevotella. These are common bacteria, but they can go rogue in immune-compromised people or when they find themselves in the wrong spot. This was a novel finding of the study, which also confirmed previous research on the connection between specific gut microbes and Parkinson’s.

Among the underrepresented good bacteria are those from the Lachnospiraceae and Ruminococcaceae families. They include species like Faecalibacterium and Roseburia that convert fiber in the diet to short-chain fatty acids like butyrate that both heal and nourish the gut lining. Interestingly, high doses of L-dopa were associated with further reduction of these butyrate-producing microbes, adding to the woes of advanced patients.

The researchers also found that a few bacteria normally considered to be healthy probiotics, such as Lactobacillus and Bifidobacteria, are sometimes elevated in Parkinson’s patients. Lactobacillus can consume L-dopa, which helps explain its growth, but that means larger doses must be prescribed, perpetuating a vicious cycle. Someone with a leaky gut or compromised immune system may not be able to withstand such a bloom in bacteria, beneficial or not. That’s a sobering thought about probiotics in general; even the safest probiotic is generally unhealthy when it’s in your blood instead of your gut. That is a good reason to avoid them if your gut is inflamed or leaky.

Establishing Causality

This research only demonstrates a correlation. It can’t tell us if the microbes cause or are caused by Parkinson’s. But a remarkable 2017 study showed that Swedish people who received vagotomies had lower rates of Parkinson’s. Vagotomies cut the vagus nerve, which was once a way to treat intractable ulcers. So, what does the vagus nerve have to do with Parkinson’s?

Could the immune system play a role? When pathogens are detected, one of the defenses is an immune stimulant called α-synuclein. When injected into a mouse gut, α-synuclein migrates up the vagus nerve to the brain where it aggregates into clumps. These clumps can be large enough to see in an optical microscope, where they were first noticed by Fritz Lewy in 1910. Lewy-body disease, which tormented Robin Williams, is related to Parkinson’s, which also involves α-synuclein. If Lewy bodies must travel from the gut to the brain before Parkinson’s symptoms show up, that strengthens the case for causality.

Growing New Neurons

Two other research groups, neither of which seemed to be aware of the other, have broken new ground by inducing the growth of new neurons in the substantia nigra. Besides neurons, brains are full of glial cells. Glia is Greek for glue, and these cells do indeed hold the brain together. There are actually many different types of glial cells, providing support and insulation, without which the brain couldn’t function. Some of them have roles in the brain’s immune system, tracking down pathogens. Others surround blood vessels in the brain and manage the blood-brain barrier.

They are also potential neurons. Binding proteins keep these glial cells moored to their supporting role like shackles. If you block them, the shackles break and the glial cells metamorphose into full-fledged neurons.

A study by Hui Yang and colleagues at Shanghai Institutes for Biological Sciences shows that a gene-editing technique called CRISPR can block the binding protein and convert glial cells into neurons. They were looking for a way to restore sight after retinal injury, and they succeeded, at least partially. But they also used their CRISPR method to convert glial cells in the substantia nigra into fresh dopamine neurons, via brain injection. In a mouse model of Parkinson’s, this alleviated motion dysfunctions.

A few weeks later, a second study was published, from Xiang-Dong Fu and colleagues at UC San Diego, who also grew new neurons that repopulated the substantia nigra and also restored normal motion in a mouse model of Parkinson’s. Instead of CRISPR, they used antisense oligonucleotides (ASOs) — snippets of DNA that stick to messenger RNA and act like sand in the molecular gears. These were also injected into the brains of the mice.

Having demonstrated that an ASO can induce the growth of new neurons and reverse Parkinson’s symptoms, the authors sounded hopeful, saying the technique supports “the feasibility of a transient, single-step strategy for treating Parkinson’s and perhaps other neurodegenerative diseases.”

These studies are remarkable for targeting the same binding protein using two different techniques and yet creating the same outcome: nerve regrowth and subsequent improvement in a mouse model of Parkinson’s.

Together, these studies offer new hope for Parkinson’s patients. One makes a compelling case for Parkinson’s starting in the gut, providing some specific microbes to monitor or target. The other two studies point to a way to repair the resulting damage by growing new neurons. All three studies are quite promising, but there is a lot of work to be done before they can be put into clinical practice. Questions include the practicality of brain injections and the possibility of health issues resulting from a depletion of the glial cells that are converted into neurons.

Watch this space.

References

Wallen, Zachary D., Mary Appah, Marissa N. Dean, Cheryl L. Sesler, Stewart A. Factor, Eric Molho, Cyrus P. Zabetian, David G. Standaert, and Haydeh Payami. “Characterizing Dysbiosis of Gut Microbiome in PD: Evidence for Overabundance of Opportunistic Pathogens.” Npj Parkinson’s Disease 6, no. 1 (June 12, 2020): 1–12.

Liu, Bojing, Fang Fang, Nancy L. Pedersen, Annika Tillander, Jonas F. Ludvigsson, Anders Ekbom, Per Svenningsson, Honglei Chen, and Karin Wirdefeldt. “Vagotomy and Parkinson Disease.” Neurology 88, no. 21 (May 23, 2017): 1996–2002.

Zhou, Haibo, Jinlin Su, Xinde Hu, Changyang Zhou, He Li, Zhaorong Chen, Qingquan Xiao, et al. “Glia-to-Neuron Conversion by CRISPR-CasRx Alleviates Symptoms of Neurological Disease in Mice.” Cell 181, no. 3 (April 30, 2020): 590-603.e16.

Qian, Hao, Xinjiang Kang, Jing Hu, Dongyang Zhang, Zhengyu Liang, Fan Meng, Xuan Zhang, et al. “Reversing a Model of Parkinson’s Disease with in Situ Converted Nigral Neurons.” Nature 582, no. 7813 (June 2020): 550–56.