Dual Functions of PME-1 Protein: Essential for Brain Development and Potential in Disease Therapy

PME-1 is a multifunctional protein that plays a vital role in cellular regulation by modifying other proteins via the removal of methyl groups. Elevated levels of PME-1 have been linked to various diseases, including Alzheimer's disease and cancer, highlighting its significance in disease pathology.

A recent study published in The FASEB Journal by researchers led by Takashi Ohama from Yamaguchi University reveals that PME-1 influences cell signaling through two distinct mechanisms that are crucial during mouse development. The first involves demethylation of the tumor suppressor complex PP2A, which is essential for proper brain development and cell regulation. The second mechanism entails PME-1 directly binding to the catalytic subunit of PP2A, thereby inhibiting its activity.

The assembly and function of PP2A, a key tumor suppressor enzyme, rely on methylation status to regulate its three subunits: catalytic, regulatory, and scaffold. PME-1 typically removes methyl groups to prevent certain regulatory subunits from associating with PP2A, impacting processes like brain development, tissue growth, and cell survival.

Using innovative genetic modifications, scientists engineered mice to carry mutations that disable specific PME-1 functions. Notably, the S156A (SA) mutant cannot demethylate but can inhibit PP2A activity through binding, while the M335D (MD) mutant can remove methyl groups but cannot inhibit PP2A. Findings showed that SA mutants had severe developmental issues, including smaller size, brain atrophy, and increased inflammation, illustrating the importance of PME-1 demethylation in healthy development. Conversely, MD mutants appeared normal at birth but displayed defective olfaction, essential for feeding behavior.

These insights suggest that PME-1’s dual functions—demethylation and enzyme inhibition—are both necessary for normal development, especially of the brain and olfactory system. Understanding these mechanisms opens avenues for targeted therapies that could modulate PP2A activity. Such treatments have potential in slowing Alzheimer’s progression, improving cognitive functions, and controlling tumor growth in certain cancers.

The study emphasizes the importance of enzyme activity-independent roles, which have been previously underappreciated, and contributes valuable knowledge toward developing novel therapeutic strategies.