Todd Cohen and Jonathan Schisler 鈥� a neuroscientist and a heart researcher 鈥� began working together in 2016 after meeting for coffee in Marsico Hall. By combining their expertise in protein studies, they strive to develop a potential treatment for Alzheimer鈥檚 disease.
They crack jokes. They interrupt each other. They finish each other鈥檚 sentences. Jonathan Schisler and Todd Cohen鈥檚 friendship might remind you of those couples from the vignettes in 鈥淲hen Harry Met Sally.鈥� When asked how they met, Schisler laughs.
鈥淲ell, Todd said we met each other years ago [at Duke], which I don鈥檛 even remember,鈥� he says.
鈥淚 knew him, but he didn鈥檛 know me,鈥� Cohen says. 鈥淚 admired him from afar. He had no clue who I was.鈥�
While they ended up going separate ways for a while, both eventually landed at 黑料网 to study proteins. As a neuroscientist, Cohen focuses on why proteins aggregate in the brain. And although Schisler, a biochemist, works in a different field, he too studies proteins 鈥� how they form and function in the heart.
Proteins are vital to a variety of processes 鈥� from transporting oxygen to transmitting messages between cells 鈥� and are required for the structure, function, and regulation of the body鈥檚 tissues and organs. So, when they stop working, problems arise. That鈥檚 what Cohen and Schisler are focused on.
鈥淢ultiple diseases can be attributed to proteins not functioning as intended, whether that鈥檚 due to mutations, stress, age, radiation. All those things impact how proteins function,鈥� Schisler says. 鈥淭hat鈥檚 why protein research is incredibly foundational to everything we study.鈥�
Current protein studies are guiding scientists down a road of endless discoveries, from like blood, human tissues, and vaccines to creating new and .
Cohen and Schisler want to know how to stop proteins from malfunctioning in order to, potentially, reverse the effects of the diseases they cause or prevent them from happening altogether. Specifically, they are looking at how faulty proteins cause Alzheimer鈥檚 disease.
Cellular workhorses
Imagine how getting behind on your laundry disrupts the synergy of your closet. Shirts drip from shelves, sweaters sit balled up in the corner, socks of all shapes and sizes lie scattered on the floor. While these piles form separately from one another, they eventually combine into one large mass of clothing.
A similar event happens with proteins in the body. When a protein fails to fold properly, it gloms onto other misfolded proteins and forms an aggregate 鈥� in other words, a big pile of stinky laundry. These clumps can become toxic and lead to diseases from cataracts to cystic fibrosis. Proteins are the workhorses for all human cells, and when they malfunction, our bodies just don鈥檛 work as well.
Schisler focuses on protein quality control within the heart. Every week, he says, heart cells produce an entirely new set of proteins that allow it to beat consistently. When these proteins stop working and begin to accumulate, heart failure occurs.
A similar thing can happen with proteins in the brain, which lead to diseases like Parkinson鈥檚, amyotrophic lateral sclerosis (ALS), Huntington鈥檚, frontal temporal dementia, and Alzheimer鈥檚. Cohen has spent the past decade trying to understand why proteins aggregate. Specifically, he focuses on a protein called tau, which is abundant in neurons.
鈥淭he field generally thinks if you prevent these proteins from clumping, you鈥檒l cure all these diseases,鈥� Cohen says. 鈥淪o if you can prevent tau from forming, you would probably prevent the cognitive impairment in Alzheimer鈥檚 disease.鈥�
But how can tau be prevented from forming? Cohen and Schisler may have a solution 鈥� one they鈥檝e been dreaming up since first meeting in 2015. That dream is now on its way to becoming reality thanks to a that the聽 received in 2019 from the National Institute on Aging in early 2019.
Protein purging
When a brain loses neurons, it鈥檚 most likely because of failed tau proteins, according to Cohen. Since 2010, he鈥檚 experimented with how different enzymes modify tau, in search of one to stop it from misfolding and forming piles upon piles of dirty laundry in the brain.
鈥淚 always joke that he鈥檚, like, in 鈥楾he Matrix鈥� looking at all these things sprinkling down the screen and it鈥檚 tau modifications,鈥� says Schisler, chuckling.
While Cohen was busy decoding tau, Schisler was working with a protein called chip that, turns out, performs a type decluttering session. Chip recruits other proteins into groups and helps them restructure. More specifically, Schisler found that chip was throwing out misfolded forms of tau in the heart. As organizing guru Marie Kondo says: If it does not spark joy, toss it.
鈥淎nd if it works in the heart,鈥� Cohen says, 鈥渨hy not the brain?鈥�
In 2016, after reading Schisler鈥檚 paper describing chip鈥檚 clean-up method, Cohen emailed him almost immediately. They met and quickly realized collaboration was imminent.
鈥淲ith Todd, I just knew,鈥� Schisler says. 鈥淟ike I knew with my wife. I thought, This is going to be a beautiful relationship.鈥�
鈥淪ome people just don鈥檛 click,鈥� Cohen admits. 鈥淓ven if it鈥檚 the right project at the right time, if you can鈥檛 meet and talk about it and it鈥檚 not the right fit, it just doesn鈥檛 happen.鈥�
Refold and reuse
While Cohen and Schisler have only been working together for a few years, their collaboration has already been a fruitful one. After running some experiments, they aren鈥檛 so convinced that chip breaks down and removes tau from the body as previously thought. Instead, they believe chip refolds tau in a way that prevents it from building up and causing problems.
鈥淐hip reshapes tau 鈥� and that鈥檚 not to be taken lightly,鈥� Cohen points out. 鈥淵ou might think, Oh, it鈥檚 just a minor incremental advance. It鈥檚 an important thing. It makes a world of difference when you鈥檙e in a brain and trying to get rid of a protein versus reshaping it. It will change how we treat patients.鈥�
If tau is so problematic, why don鈥檛 we just remove it? Well, it鈥檚 one of the most abundant proteins in the body. And, according to Cohen, researchers still don鈥檛 really know what it does beyond providing some stabilization within neurons, so getting rid of it could harm cells in the long term.
鈥淭here are companies trying to remove it completely,鈥� Cohen says. 鈥淏ut the problem is, if it鈥檚 really important in providing some stability function, you could imagine that people who don鈥檛 have tau might have some longer-term problems.鈥�
To further explore the purpose of tau, Cohen and Schisler are using their recent grant to run a large-scale study on mice with Alzheimer鈥檚 disease. Across their lifecycle, they will administer chip to observe how it affects tau at different stages of the disease.
If a chip therapy is utilized in patients with early-onset Alzheimer鈥檚, could it stop the disease from progressing?聽 鈥淭hat would be cool,鈥� Schisler says. 鈥淏ut, to me, the bigger, more exciting question is this: Can we take an animal that already has this bad tau and get rid of it? We want to know if we can affect the disease after it鈥檚 already started.鈥�
Since most doctors aren鈥檛 searching for signs of Alzheimer鈥檚 in younger patients, catching it early is rare 鈥� and getting an accurate diagnosis can be frustrating. A diagnosis is more likely to occur in the middle of the disease鈥檚 progression. The ability to revert or stop the damage that鈥檚 already been done would be a game-changer.
For Cohen and Schisler, the game has just begun. They will spend the next two years continuing to study chip and tau, working to ultimately develop a treatment for Alzheimer鈥檚. They are grateful they don鈥檛 have to take on the task alone.
Jonathan Schisler is a research assistant professor in the Department of Pharmacology and the Department of Pathology and Laboratory Medicine within the 黑料网. He is also a member of the McAllister Heart Institute.
Todd Cohen is an assistant professor in the Department of Neurology within the 黑料网 and a member of the 黑料网 Neuroscience Center. He is also an adjunct assistant professor in the Department of Biochemistry and Biophysics in the 黑料网.
News courtesy of Alyssa LaFaro, 黑料网 Research.