Yale News

Three Yale researchers have been awarded grants by the Chan Zuckerberg Initiative, or CZI, to research neurodegenerative diseases — disorders characterized by the molecular unraveling of  the central nervous system, including Alzheimer’s and Parkinson’s diseases.

The three researchers are among 30 pairs of scientists being funded by the initiative to conduct research as part of the Neurodegeneration Challenge Network, or NDCN, which aims to connect professionals from different disciplines and to encourage collaboration between more experienced scientists and those who are at earlier stages of their careers. As such, neuroscience professor Pietro De Camilli and assistant professor of cellular and molecular physiology Hongying Shen GRD ’13 will be joining forces on a project that studies how dysfunction in the metabolism of mitochondria and lipid transport proteins might instigate neurodegenerative disorders. Elsewhere at the medical school, associate professor of genetics and neuroscience Marc Hammarlund will collaborate with Gulcin Pekkurnaz, assistant professor of neurobiology at the University of California, San Diego, to explore pathways governing energy balance in healthy neurons and how defects within them can lead to these illnesses.

“I was surprised [to receive this grant] because the CZI awards are usually highly competitive,” Shen wrote in an email to the News. “I was very delighted that I can be part of [this] collaborative, science community.”

According to the CZI website, awardees were selected based on the scientific quality of their teams, the transformative potential of their proposals and the possible outcomes that they could ignite. Pekkurnaz, who echoed Shen’s surprise, added that the grant was pivotal in bringing their scientific plans into fruition.

“We all can have great ideas,” Pekkurnaz wrote. “But without the funding support, they just stay as dreams.”

The CZI was co-founded in 2015 by pediatrician Priscilla Chan and Facebook CEO Mark Zuckerberg. The initiative focuses on four core areas: education, social justice, science and community initiatives. According to their website, the initiative was established to promote collaboration and community-driven solutions for different kinds of challenges, including the eradication of diseases. When it comes to neurodegenerative disorders, the fact that there is currently no effective cure makes them a top scientific priority.

“While there has been significant investment in neurodegenerative disease research, our understanding of the underlying cellular mechanisms and basic biology of most of these disorders is limited,” the CZI website reads. “The goal of the Neurodegeneration Challenge Network is to bring together outstanding, innovative, forward-thinking scientists from different disciplines, into a collaborative network to work together on questions related to the basic cell biological mechanisms of neurodegeneration in the context of human disease biology.” 

Even though the three Yale-associated research projects have slightly different focuses, their interests are all fundamentally related to the mitochondria — little structures within cells that play a fundamental role in generating the energy that sustains life. 

According to De Camilli, in contrast to other cellular components, mitochondria do not dialogue with surrounding structures through membrane trafficking — a process of biochemical signaling that relies on tiny sacs called vesicles. Instead, they retain a certain degree of autonomy. This is due to their evolution from bacteria that invaded cells billions of years ago and eventually became the mitochondria we are familiar with today.

Even though mitochondria function somewhat independently from the other parts of the cell, De Camilli said they are still able to sustain constant communication with other cell structures, especially with the endoplasmic reticulum — a network of membranes that is involved in the production of proteins and lipids. This observation sparked his interest in the mechanisms that enable this intricate interaction between these organelles.

“I am studying the role of proteins implicated in this cross-talk, and more specifically proteins that tether the ER to mitochondria and mediate exchange of lipids between the two organelles,” he said.

According to De Camilli, it is important to study mitochondrial function within the context of neurodegenerative diseases because defects in mitochondria have been linked to cell degeneration and death.

“In most tissues, cell death can be compensated by cell renewal,” De Camilli wrote. “Neurons, however, last all life, and if they die they cannot be renewed. 

Knowing that mitochondrial defects can culminate in the death of brain cells raises the question of how they become dysfunctional in the first place. A better understanding of the mechanism by which mitochondria break down would help paint a clearer picture of how neurodegenerative disorders arise.

“Mitochondrial deterioration is the hallmark of aging and age-related neurodegeneration,” Shen wrote to the News. “It would be of great importance to dissect the exact mitochondrial perturbations and the metabolic pathways that would eventually lead to [neurodegenerative] diseases.”

According to Shen, even though human genes code for different metabolic enzymes, our primitive understanding of them is a testament to the insufficient attention that has been placed on unpacking their biological role in disease development. 

Building upon evidence that has shown that mutations affecting lipid metabolism may be connected to neurodegenerative disease, Shen hopes to shed light on how lipids are metabolized, regulated and distributed within the cell.

Hammarlund and Pekkurnaz, the other Yale-associated duo that has been granted an award, will also research how mitochondrial failure is linked to neurodegeneration through a different lens. Through the use of mouse and invertebrate systems, they will try to understand the pathways that maintain constant energy levels in typical neurons to shed light on how defective energy balance can contribute to neurodegeneration.

“A better understanding of how neurons regulate their spatiotemporal energy balance will help us discover how they become faulty in neurodegenerative diseases,” Pekkurnaz wrote. “This project focuses on in vivo cell-biological cross-species studies, and such studies have the best potential to identify mechanisms that function outside the laboratory in human health and disease.”

Pekkurnaz’s lab at UC San Diego focuses on the different roles played by mitochondria on many cell types. Despite their nickname as “the powerhouse of the cell,” mitochondria can carry out other cell-specific functions too, including stabilizing the concentration of calcium ions within cells and influencing neurotransmitter metabolism. Researchers in Pekkurnaz’s lab use interdisciplinary approaches to study the metabolic processes of the cell in typical and atypical conditions.

Hammarlund’s research, on the other hand, focuses on neurons themselves. He studies how neurons decide their fate, in addition to neuronal circuits and axon regeneration, and uses these mechanisms to understand how they come into play during neurodegeneration. 

In both collaborations, scientists will be leveraging their own expertise and experience to collaboratively uncover different pieces of the neurodegeneration puzzle. 

According to the Burke Neurological Institute, somebody in the United States develops Alzheimer’s disease every 65 seconds.