Targeting PME-1 may offer new strategies for treating neurological disorders and cancer

PME-1 is a protein that modifies other proteins by removing methyl groups, but high levels of PME-1 are observed in some diseases, including Alzheimer's disease (AD) and cancer. In a recent study published in The FASEB Journal, researchers found that PME-1 can affect cell signaling downstream of the tumor suppressor complex PP2A in two distinct ways: by removing methylation and by direct binding. This work could pave the way for more effective AD and cancer treatments.

The addition of methyl groups is important for the assembly of the signaling complex PP2A, a tumor suppressor enzyme involved in brain development, cell growth, and survival. PP2A consists of three subunits: catalytic, regulatory, and scaffold. The methylesterase PME-1 removes methyl groups, which prevents certain regulatory subunits from joining the complex. However, research has also shown that PME-1 can interact with these complexes using another strategy: PME-1 can inhibit PP2A by binding to its catalytic subunit, directly disrupting its activity.

Recently, Takashi Ohama and colleagues at Yamaguchi University and several institutions in Japan demonstrated that specific point mutations could destroy one of PME-1's activities without interfering with the other in in vitro tests. For example, the PME-1 S156A mutant (called SA) is unable to remove methyl groups, but can still inhibit PP2A by inhibiting catalytic activity. The PME-1 M335D mutant (called MD), on the other hand, can remove methyl groups to alter regulatory subunit assembly but can't inhibit PP2A activity.

In the current study, Ohama's team developed genetically modified mice carrying these mutations to study their effects in a complete organism. They found SA mutant embryos were smaller than wild-type and were not viable at birth. In late embryonic stages, these mutants had atrophied skeletal muscle and smaller brains with a small and disorganized cerebellum. Other experiments revealed an upregulation of inflammatory factors and an increase in apoptotic cells throughout the body, including in the brain. Compared to wild-type embryonic fibroblasts, fibroblasts from the SA mutant mice grew slowly, and also had elevated levels of damaging reactive oxygen species and more mitochondria that were more active. 

Unlike SA mutants, the mice with the MD mutation lived for two days after birth. Although the mice looked like wild-type pups, they did not try to suckle and lacked milk in their stomachs. In olfaction tests, the researchers determined that the pups had an abnormal sense of smell, which is necessary for the pups to find their mother's milk. Embryonic fibroblasts from these mutants grew normally.

The results show that PME-1 demethylation is critical for normal development, especially for the brain, whereas PME-1 binding is required for the development of olfaction.

This dual role helps explain how PME-1 precisely regulates PP2A in different biological contexts. Additionally, this study highlights the importance of activity–independent functions of enzymes, which may have been overlooked in classical knockout mouse models."

Takashi Ohama, Yamaguchi University

The findings could have benefits for patients in the future, leading to drugs that could restore or fine-tune PP2A activity. "Such treatments could potentially slow disease progression or improve brain function in patients with Alzheimer's disease or reduce growth in certain cancers," Ohama explains.