Biology of p97 protein in neurodegenerative disease

February 21, 2023 | Biology

p97 protein’s role in the human body includes disposing of proteins that are already past their shelf life. They work with co-factors or binding partners which help them target proteins that need to be eliminated. In a study conducted by experts from the Tufts University School of Medicine, they’ve disclosed the fundamental biology of p97 while emphasizing its role on keeping cellular organelles in sync with one another.

The research team discovered that p97, in coordination with one of its cofactors UBXD8, controls the type of proteins that are present where the mitochondria and endoplasmic reticulum (ER) meet. These contacts, which are very sensitive to disturbances, allow the organelles to provide signals or transfer cargo. If the p97-UBXD8 complex is absent, certain molecules aggregate on the ER membranes, causing them to stick to the mitochondria.

Surprisingly, findings indicated that the accumulated molecules at these contacts transmitted information, causing the membranes to go rigid. The team figured that they could alter the relative rigidity of the membranes at these contacts, thus regulating how these contacts formed and dissipated.

Malavika Raman, senior author of the study, thought about how neurodegenerative diseases (such as ALS and dementia) are caused by p97 mutations in terms of proteins not getting disposed of and how this study further suggested that p97 mutation can also lead to miscommunication between organelles.

For their experiment, the research team used mouse models of p97 mutants that cause neurodegeneration. Results confirmed and were parallel - the proteins they found to be changing at these contacts were also altered in the brains of mice. Disruption of contacts and inherent lipid synthesis/metabolism are the emerging hallmarks and contributors for the variety of human disorders such as neurodegeneration.

With these conclusions, the team explores human neurons and what happens when there are p97 mutations and what can be done to help these neurons survive.