GPS-like system of cells and its potential implications in neurodegenerative diseases

15 Dec 2017

GPS-like system of cells and its potential implications in neurodegenerative diseases


By Prof Raghu Padinjat, Senior Fellow

National Centre for Biological Sciences, Bangalore

Living cells are constructed from biomolecules such as proteins, lipids and carbohydrates that are required for normal function. Every cell has a unique composition, i.e. it is put together from a specific set of molecules. In addition, these molecules need to be positioned at the correct locations within the 3D organization in the cell. How does this work and what are the consequences of not placing a protein in the correct location?

In a recently published study from my group, we investigated the localization of a protein called RDGB that acts as a ferry moving lipid molecules from the interior of the cell to the surface membrane. We studied this in a fruit fly (Drosophila) system. The presence of the correct amounts of the right lipids at the plasma membrane is important for normal cell function. Inappropriate control of lipid levels at the cell membrane results in many human diseases. Genetic disorders such as mutations in the PTEN gene alters the lipid composition of the plasma membrane and frequently results in human cancers. Understanding how molecules such as RDGB control lipid composition may help develop new ways of treating cancers.

The study provides an insight into the importance of correctly localizing the RDGB protein. They also identified the components of the GPS system that the cell uses to locate the RDGB protein precisely where it is required.

Experiments revealed that it is important to correctly localize the RDGB protein to a very unique part of the cell. In the absence of such correct localization the photoreceptor cells do not function normally; in this case fail to respond to light and undergo degeneration. They have found some key parts of the cellular GPS system that help in correct localization and also the signals within the RDGB protein that are read by the GPS system.

One key component of the GPS system that localizes RDGB is the protein VAP. Mutations in human VAP have been identified in cases of the fatal human neurodegenerative disease called Amyotrophic Lateral sclerosis (ALS). However, we still do not know why the motor neurons of individuals with ALS undergo degeneration. Studies such as ours provide new insights into why patients with ALS undergo neurodegeneration leading to possible treatments. Presently there is no treatment for ALS.

RDGBα localization and function at a membrane contact site is regulated by FFAT/VAP interactions. Shweta Yadav, Rajan Thakur, Plamen Georgiev, Senthilkumar Deivasigamani, Harini K, Girish Ratnaparkhi, Padinjat Raghu. Journal of Cell Science. November 2017.

Media report- Understanding Positioning System Of Cells May Help Unravel Key Diseases. India Science Wire

Banner image description: Confocal microscopy image through the Drosophila retina showing the ommatidia that make up the compound eye. Photosensitive plasma membrane marked with phalloidin is shown in red. The RDGB protein arranged precisely at the base of the plasma membrane is stained in green. At this membrane contact site,  RDGB transfers lipids between the endoplasmic reticulum and plasma membrane thus controlloing its lipid composition.