Blocking Two Proteins Linked to UBE3A Activity Might Treat Angelman, Study Suggests
Lowering the levels of two proteins involved in nerve cell development and tightly linked to the activity of UBE3A — the enzyme that is faulty in Angelman syndrome — could be an attractive way of reversing the deficits in nerve cell communication that characterize UBE3A-related disorders, according to a recent study.
The study, “UBE3A-mediated PTPA ubiquitination and degradation regulate PP2A activity and dendritic spine morphology,” was published in the journal PNAS.
Angelman syndrome is characterized by the abnormal activation or loss of some regions of the UBE3A gene copy inherited from the mother.
UBE3A is known to play a critical role in the development of specific brain cells (neurons), allowing them to establish the connections necessary to forming the natural neural circuit wiring within the brain. However, the mechanisms that connect changes in UBE3A protein levels, whose production the gene instructs, to neurodevelopmental disorders are not well understood.
Protein phosphatase 2A (PP2A) is another protein crucial for the correct development of the nervous system. PP2A is an enzyme that is crucial for the growth and differentiation of nerve cells as well as synaptic plasticity. While synapses are the junctions between two nerve cells that allow them to communicate, synaptic plasticity refers to the ability of synapses to strengthen or weaken over time.
Researchers found that when they forced the production of UBE3A nerve cells grown in the lab, the activity of PP2A enzyme dramatically fell. In contrast, loss of UBE3A function led to greater PP2A activity. This was also true for brain cells derived from mice lacking the Ube3a protein – an experimental model of Angelman syndrome.
Despite these data suggesting a connection between the two proteins, the team did not find evidence that these two proteins were directly interacting.
Additional experiments showed that UBE3A could regulate the levels of a protein called phosphotyrosyl phosphatase activator (PTPA) protein — an activator of PP2A — which in turn directly interacted with the PP2A enzyme and modulated its activity. Importantly, PTPA was a substrate of the UBE3A enzyme (a substrate is a molecule upon which an enzyme acts).
Using brain cells collected from Angelman mice, the team confirmed that PTPA levels and PP2A activity were both higher in these animals when compared with healthy controls.
Further analysis demonstrated that increased levels of PTPA would mimic the effect of UBE3A loss, resulting in structurally aberrant and less differentiated neurons during development. In contrast, chemically inhibiting the PP2A enzyme in brain tissue samples taken from Angelman mice improved neuronal communication patterns.
Importantly, treatment with a PP2A inhibitor (LB100), administrated by injection every two days, significantly improved gait patterns, muscle strength, and learning skills in the diseased mice.
“Our findings offer an important mechanistic link between impaired PP2A activity and synaptic and behavioral deficits in UBE3A-related neurodevelopmental disorders,” the researchers wrote.
These results suggest that “PP2A inhibitors could be used to ameliorate cellular and behavioral deficits induced by UBE3A deficiency,” they added.