This week, we highlight two recent publications in MedZine. One of them is a publication in Cell by researchers of the John Hopkins Institue for Cell Engineering. The cell biologists from Baltimore performed pioneering research into the mechanisms behing the onset of Parkinson’s disease (PD) by a mutation in LRRK2. The other article, by scientists of the McGill University of Montreal published in Immunity, deals with the role of prostaglandin E2 (PGE2) in influenza A infection. The researchers showed that inhibition of PGE2 causes an increase in the survival rate of mice, when infected with a lethal dose of the influenza virus.
Neurodegeneration through LRRK2 unraveled
Martin and colleagues describe the mechanism that is involved in de generation of PD by mutations in the leucine-rich kinase 2 (LRRK2) gen. The researchers showed that mutated LRRK2 causes increased phosphorylation of the ribosomal protein s15. This causes protein accumulation in neurons of the substantia nigra leading to cell death of these dopamine-producing neurons. This can lead to PD.
It has been clear for some time that mutated LRRK2 plays a role in the neurodegeneration that causes PD. Until now, the cascade behind this phenomenon was unknown. When LRRK2 is mutated at G2019S, s15 is disproportionally phosphorylated and this leads to excessive protein production. Accumulation of proteins in neurons causes cell death.
LRRK2 mutations are known to cause PD and in certain populations these mutations are responsible for up to 40 percent of the PD cases. Providing insight into the mechanism behind this could provide opportunities for the development of new PD therapies.
Influenza and PGE2
Coulombe and colleagues investigated the role of prostaglandin E2 (PGE2) in the immune response to influenza A virus (IAV). Researchers came up with the idea to investigate the effects of increased PGE2 by observing the anti-inflammatory function of aspirin, which inhibits PGE2 production. IAV infection causes an increase in PGE2 levels. PGE2 inhibits the recruitment of macrophages to the lungs. In addition, the interferon production and apoptosis of infected macrophages is decreased. Also adaptive immunity is inhibited since antigen presentation by macrophages is decreased. Together, these effects of PGE2 cause an impaired response to an IAV infection.
Flu epidemics cause millions of victims worldwide every year, despite large-scale efforts made by vaccination programs. Maziar Divangahi, senior author of the article, thinks that, because prostaglandin inhibitors are already developed, a fast clinical transition to a functional therapy could be made. Moreover, Divangahi thinks that these results could be important for the treatment of other forms of influenza and possibly even infection with other viruses.
Sources: Cell and Immunity