Study sheds new light on crucial proteins linked to genetic diseases

A new study, performed at Chapman University, offers a better understanding of the properties of important proteins found inside the ciliary membrane. These proteins play crucial roles in cardiovascular functions and human genetic diseases.

Ashraf Mohieldin, postdoctoral fellow at Chapman University and principal investigator of the study, led a team to examine and analyze the structure of primary cilia to better comprehend ciliary bulbs and its significance. Image Credit: Chapman University.

Scientists have recently demonstrated that primary cilium, an organelle present on the surface of nearly every type of cells in the body and also called ciliary bulbs, exhibits membrane swelling. The physiological relevance and structure of this organelle continue to be elusive.

Ashraf Mohieldin, PhD, the principal investigator of the study and postdoctoral fellow from the School of Pharmacy at Chapman University, headed a research team to investigate and examine the structure of primary cilia to further interpret ciliary bulbs and its importance.

Through proteomic identification and a single-cell, single-cilium imaging method, the researchers found that a ciliary bulb has characteristics similar to extracellular vesicles (EVs).

Information within the cardiovascular cells is facilitated by EVs. Mohieldin’s research team discovered that ciliary extracellular-like vesicles, or cELVs, share analogous characteristics with EVs, and that they play a particular role in cellular functions, ciliary signaling, as well as in preserving cardiovascular homeostasis.

These sensory proteins are present in the membrane of primary cilia and identify signals from other types of cells and in the neighboring environment. The signal detection of the protein acts as cellular compartments that control crucial signaling routes and activates the behavior and response of the cell.

The researchers also assessed a database of 172 cELV proteins and noted that the cELV protein has a special and dynamic movement and also the potential to be discharged by mechanical fluid force.

Impairment in the primary cilia has been linked to various genetic disorders, known as ciliopathies, including Bardet-Biedl syndrome, Joubert syndrome, Meckel-Gruber syndrome, and polycystic kidney disease. Ciliopathies are usually life-threatening and chronically disabling conditions that affect numerous organ systems.

Our findings reveal for the first time crucial ciliary proteins that are implicated in ciliopathy disorders. We hope that our research will rejuvenate our understanding and current approach to investigate human genetic diseases.”

Ashraf Mohieldin, PhD, Principal Investigator and Postdoctoral Fellow, School of Pharmacy, Chapman University

Dr Mohieldin’s laboratory examined mice and zebrafish to screen abnormal function of the cELV proteins and the role played by protein in cardiovascular systems. The team noted cystic kidney disorders, hydrocephalus, and randomized heart looping in the zebrafish. They also looked at compensated heart contractility in the mice and zebrafish to verify and compare the information.

Through this, the researchers noticed that low circulation of cELVs leads to arrhythmogenic characteristics, hypotension with compensated heart function, cardiac fibrosis, and left ventricular hypertrophy, resulting in a high mortality rate in mice.

Moreover, the overall ejection fraction, cardiac output, and stroke volume are considerably decreased in mice that lack the cELV protein. No prior studies were able to identify the physiological functions of the cELV protein in mouse and zebrafish model, until now.

After discovering the powerful association between the cELV protein and cardiovascular function and ciliopathies, the team believes that upcoming studies will target these proteins to help determine a feasible treatment for medical disorders related to cilia dysfunction.

Targeting these proteins can help scientists to clearly understand the mechanism of these disorders and ultimately lead the path to potential treatments for ciliopathies.”

Ashraf Mohieldin, PhD, Principal Investigator and Postdoctoral Fellow, School of Pharmacy, Chapman University