Ask a Caltech Expert: Viviana Gradinaru on Neurodegenerative Diseases

Neurodegenerative diseases often cause very gradual damage to the brain and nervous system. Is it possible to detect them before physical or cognitive symptoms emerge?

There are detectable markers of neurodegeneration in the brain and body. The challenge is that it is very hard to measure those markers through noninvasive methods. By the time neurodegeneration is detected through changed behavior, the cellular mechanisms have been underway for a long time.

There are a few ways you can get a head start on detection. First, some genetic mutations can be tested for earlier. PET scan tracers can also detect cellular signs of Alzheimer's disease in a noninvasive way. Additionally, there is a new test being developed for Parkinson's in which cerebrospinal fluid is collected through a spinal tap. The fluid is then analyzed in a process that amplifies and detects aggregated alpha-synuclein, the toxic molecular component that causes Parkinson's. We might be able to use this test to detect Parkinson's and monitor patients' responses to different interventions.

What is happening at the cellular level in patients with neurodegenerative diseases?

Neurodegenerative disorders have different manifestations. Many of them have their origin in misfolded or aggregation-prone proteins, i.e., aberrant, nonfunctional, or harmful proteins. In the best case, they are mute: they do not perform their function. In the worst case, they actually gain a harmful function.

There are cellular repair processes that try to deal with that misfolding or aggregation in various ways. The cell tends to cope with misfolded proteins like we deal with the trash. The cell gathers all these faulty proteins and dumps them in the lysosomes, where enzymes are supposed to chew them up and dispose of them.

However, too many faulty proteins can lead to a balance issue: at some point, you can accumulate more trash than you can deal with.

In the brains of patients with Alzheimer's, for example, amyloid protein accumulation can be seen and measured through PET imaging.

Are there risk factors associated with protein misfolding?

Genetics is one factor. But one can develop neurodegeneration without obvious risk factors. Just as people can get breast cancer without having it in their genes, we can get neurodegeneration without obvious factors.

Let's take the case of Parkinson's. It's one disease, but there are so many ways to get to it.

It could be genetic, through mutations in a variety of genes.

There also are environmental factors. Pesticides, for example. There has been a significant link to Parkinson's in farming communities where pesticides such as rotenone are being used. Ingestion of toxins can trigger these aggregation processes in the body that then propagate to the brain.

Aging is also a risk factor. The more of these risk factors you add—if you have a genetic predisposition, if you've worked in a toxic environment, if you've eaten or inhaled toxins, if you're older—the more likely they are to put a person over the threshold for developing neurodegeneration.

Concerning toxins, researchers are finding microplastics in human brains. What are your thoughts about that?

There's an increasing realization that if we pollute the oceans, the resulting microplastics in the oceans can make it into our food supply through fish, for example.

There are various ways for microplastics to get to the brain. One is the gut; microplastics might travel through the associated nerves into the brain or make their way there from the olfactory system when they are inhaled. Another is circulation. Even though the brain is protected by the blood–brain barrier, molecules can get through. (Think of caffeine!)

Definitely, more research is needed on how our polluting our waters might lead to the ingestion of microplastics and how this might take an additional toll on our health, including effects on the brain.

While this is concerning and needs to be looked at and understood, remember that the human body is resilient. For example, our immune system constantly protects us against disease.

Are there myths about neurodegenerative disorders you'd like to debunk?

One challenge is to avoid thinking about these simply as brain disorders. Researchers are learning more and more about how the brain sits within the body and that there is important two-way communication between the brain and the gut. The state of our enteric nervous system can have a profound effect on what happens in the brain. That's on the problem side. On the solution side, the enteric nervous system could also be a much more convenient way to get to the brain than brain surgery.

My colleague Sarkis Mazmanian [Luis B. and Nelly Soux Professor of Microbiology, Merkin Institute Professor] has a thriving research program on the gut microbiome. At Caltech, he and I and David Van Valen [Assistant Professor of Biology and Biological Engineering, Heritage Medical Research Institute Investigator, Howard Hughes Medical Institute Freeman Hrabowski Scholar], who advances machine learning and cellular analysis techniques, are part of a network called Aligning Science Across Parkinson's (ASAP), comprising scientists around the world who collaborate to understand Parkinson's and drive cures.

What developments in the understanding and treatment of neurodegenerative disorders do you find most promising?

It's a very exciting decade. Through work from many people over many years, we have learned so much about what causes neurodegenerative processes and resulting behavioral deficits, whether motor or cognitive or both. Recently, the picture has changed to where we can actually do something about it.

Antibody treatments

Promising examples of antibody treatments are accumulating, such as the antibody donanemab from Eli Lilly that has been in the news recently. It's the first example of an approved solution for Alzheimer's that not only decreases the amyloid but reduces cognitive decline by a significant percentage. Of course, there's still room for improvement. Some patients might develop side effects and complications. Understanding how to minimize these risks can allow more and more patients to benefit from such developments. It's exciting to think that we can work toward more efficient and safer delivery of therapeutics to the brain. At Caltech, we are discovering receptors in the blood-brain barrier that can act as gates for treatments. If you can load therapeutics onto these specific receptors, you can use a lower dose and still get enough medicine where it's needed, and there are fewer side effects.

Enabling brain gene therapy with better delivery vehicles

Beyond antibody treatment, another area that I'm excited about is gene therapy. If you know the genetic risk factors, you can go in and fix the gene. Replace it. Correct it. Through gene editing, silencing, and replacement, now we can do all of this.

In part through work done at Caltech, we have unlocked the ability to cross the blood–brain barrier and deliver genetic products brain-wide in a way that can bypass brain surgery.

Traditionally, to deliver research tools or therapies into the brain, you had to drill through the skull and use a needle to inject a product into the brain matter, which causes inflammation and has limited spread, reducing effectiveness. You also risk injecting either a toxic amount of product or too little to function. Now, instead, we can reach the necessary areas of the brain with a simple intravenous injection in the arm.

There are experimental therapies based on my lab's research being pursued now, including by Caltech start-up Capsida Biotherapeutics. Capsida has launched two noninvasive gene therapies: a treatment to replace the GCase enzyme in Parkinson's patients and a product that corrects a mutation to treat a form of epilepsy.

With a better understanding of how to cross the blood–brain barrier without resorting to brain surgery, as well as increasing knowledge of the genetic causes of disorders and our growing ability to do gene therapy, there are clear paths toward helping patients and even preventing illness from occurring in healthy patients. Some people even call gene therapy a cure. Unlike the antibody approaches where the patient needs to keep taking medicine, if gene therapy is effective, it's a one-and-done approach.

Optogenetics for precise neuromodulation

We also work on an approach that uses microbial opsins. One treatment option for Parkinson's is deep-brain stimulation. This invasive surgery works well for many patients, but the electrical stimulation affects all cellular circuits in the brain, whether they have to do with the disease or not. Microbial opsins could focus deep-brain stimulation treatments on targeted cells. Already, opsins are being tested for vision restoration. In the future, we might see circuit therapies that tune the cells' activity using opsins. We could see precise deep-brain stimulators for neurodegeneration or even for psychiatric disorders in addition to vision implants.

Recent progress on treatments is very exciting to witness. It's one thing to do the research and publish papers. Many times, it takes decades and decades to see the path that can benefit patients, but I think brain science has accelerated, in part because of a decade of active investment through the National Institutes of Health Brain Initiative. It is now so much easier to connect the dots and get the best minds to work on these problems to, ultimately, improve human health for all.

—Viviana Gradinaru, the Lois and Victor Troendle Professor of Neuroscience and Biological Engineering; Howard Hughes Medical Institute Investigator (selected 2024); Director of the Center for Molecular and Cellular Neuroscience; and the Director and Allen V. C. Davis and Lenabelle Davis Leadership Chair of the Richard N. Merkin Institute for Translational Research

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