Science: Presynaptic Ube3a E3 Ligase Facilitates Synaptic Elimination by Suppressing BMP Signaling
In a recent study, scientists from the University of Tokyo in Japan have made a significant breakthrough by uncovering how presynaptic Ube3a E3 ligase is involved in the removal of synapses. This research has provided important clues for future drug development in the treatment of Angelman syndrome.
Neurons communicate through synapses, which are the points of connection where information is transmitted via electrical signals. After birth, the number of synapses increases, but during childhood, the brain gradually prunes away unnecessary synapses to achieve functional maturity. However, developmental issues in the nervous system can sometimes lead to developmental disorders.
Angelman syndrome is a rare genetic disorder that negatively impacts neuronal development, leading to physical and intellectual disabilities. In Angelman syndrome patients, a gene called Ube3a doesn't function properly, hindering the elimination of synapses during development. On the other hand, abnormally high levels of Ube3a can lead to premature synaptic elimination, possibly contributing to autism spectrum disorders.
Previously, little was known about the mechanisms through which Ube3a in presynaptic neurons triggers synaptic defects, partly due to technical challenges associated with studying neural circuits in mammalian brain development.
This research team conducted studies on sensory neurons in the fruit fly Drosophila and successfully identified Ube3a and its internal workings. This has contributed to their understanding of Ube3a's role in synaptic elimination.
Fig.2 Ube3a in synaptic elimination. (From Science, 2023, doi:10.1126/science.ade8978)
The researchers found that Ube3a promotes synaptic elimination by degrading a presynaptic receptor called bone morphogenetic protein (BMP) receptor. Disrupting this process leads to an abnormal increase in the number of synapses. Consequently, future treatments for Angelman syndrome may focus on targeting BMP receptors.
This study is the first to reveal how the absence of presynaptic Ube3a E3 ligase disrupts synaptic pruning. This discovery introduces a new mechanism explaining how gene mutations and abnormal Ube3a levels can impair synaptic transmission and hinder brain maturation. It holds promise for providing new therapeutic avenues to improve the lives of Angelman syndrome patients.
More information: Furusawa, Kotaro, et al. "Presynaptic Ube3a E3 ligase promotes synapse elimination through down-regulation of BMP signaling." Science 381.6663 (2023): 1197-1205.