The recent research published in Science has uncovered a surprising function of the 19S proteasome particle in synapses, shedding new light on brain science. Traditionally, the 19S particle was known for its role in protein degradation within the proteasome complex, where it collaborates with the catalytic 20S particle to eliminate unwanted or damaged proteins. However, this study revealed that the 19S particle can also function independently in synapses, playing a regulatory role in modulating key synaptic proteins and enabling synapses to adapt to different circumstances.
Using super-resolution microscopy, the researchers observed an abundance of free 19S particles near synapses in rat cortical neurons. These autonomous 19S particles retained deubiquitylating activity, which means they can remove ubiquitin molecules from target proteins. Specifically, the 19S particles deubiquitylated lysine 63-ubiquitin (Lys63-ub), a non-proteasome-targeting ubiquitin linkage. The interaction between the free 19S particles and Lys63-ub revealed a moonlighting function of the regulatory proteasomal subcomplex near synapses.
Further experiments showed that inhibiting the deubiquitylase activity of the 19S particles significantly altered excitatory synaptic transmission and reduced the availability of AMPA receptors at multiple trafficking points, independent of the proteasome. This implies that the free 19S particles have a direct impact on synaptic plasticity and neurotransmitter signaling. The discovery of this unforeseen function of the 19S proteasome particle opens up new avenues for understanding the regulation of synapses and potentially developing therapeutic strategies for neurological disorders such as Parkinson’s disease and dementia.
In conclusion, the recent research highlights the unexpected role of the 19S proteasome particle in synapses, where it acts independently and regulates key synaptic proteins. This finding expands our understanding of protein function at synapses and offers new possibilities for studying and treating neurological conditions.