‘You can literally lose who you are’

In the “Research Matters” series, we visit labs across campus to hear directly from Stanford scientists about what they’re working on, how it could advance human health and well-being, and why universities are critical players in the nation’s innovation ecosystem. The following are the researchers’ own words, edited and condensed for clarity.

I’ve heard from a Parkinson’s patient who said, “I’m totally fine with whatever happens to my body, as long as I wake up each morning and know who I am.” That’s incredibly powerful. Especially as some of my relatives are of the age of developing these diseases, that’s been a strong motivation for me to try to understand neurodegenerative diseases and identify a cure.

A characteristic of many neurodegenerative diseases is neuron death, so my lab is trying to understand what exactly goes awry in cells to cause this death. You can think of our cells as a city. In a city, you produce waste that should be recycled. But if the recycling center doesn’t function properly, over time, the city will become overcrowded with debris and dysfunctional.

Well, inside your cells, there is an organelle called a lysosome, and it is responsible for this exact recycling function. All the trash – other faulty organelles, dysfunctional proteins, pieces of other biomolecules – will end up in the lysosome to be recycled and have their parts reused by the cell. Unprocessed, this trash can become toxic, and if these lysosomes become dysfunctional and don’t do their job, the toxins will accumulate in the cells, and the cells will start to suffer and die. One of the major cells that are affected by lysosomal dysfunction is neurons. And once they die, they can’t even renew, and this can lead to the onset of neurodegenerative diseases.

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For lysosomes to function, they require a very important lipid molecule called BMP. Very little was known about how BMP is made or how it itself is degraded. In the last few years, my lab was able to find the enzyme that makes BMP, called CLN5, and also the enzyme that degrades it, called PLA2G15. We thought that if we could boost BMP levels, we could rescue the function of lysosomes. And in experiments with animal models, we’ve been able to do just that.

We believe that boosting BMP levels has therapeutic potential across many neurodegenerative diseases, including frontotemporal dementia, certain forms of Parkinson’s disease, and Alzheimer’s. We hope that we can move toward developing small therapeutic molecules that would target these enzymes and boost BMP levels, and hopefully treat or ameliorate the symptoms in these diseases.

An important aspect of all of this is that for more than 50 years, scientists thought that BMP was a stable lipid inside the lysosome and that it didn’t degrade. But we set on this path of rescuing lysosome function when one of my students walked into my office and told me, “I think that the lysosomal enzyme PLA2G15 degrades BMP.” This is a great example of the other major mission of academic institutions: We train the next generation of scientists. Academia is the only place where you can really invest in people and train them.

I benefited from this personally. As a junior faculty member, I was funded by the NIH through the New Innovator Award, which allowed me to set up the infrastructure for most of the work that we do in the lab today. Funding fundamental science is very important, especially when we are facing all these diseases that have literally no cure, and understanding their basic mechanisms is a very long and demanding process.

I really want to emphasize that basic science like this is mostly done at academic institutions. Usually, it’s very hard for companies and industry to invest in basic science; they are really important in the second stage where they take these fundamental discoveries toward therapeutics. But without the freedom that we have in academia, it would be really, really hard to do the kind of science that is essential for any sort of major breakthrough.