The proteasome, the system that breaks down proteins, altered the pace of neuronal development in mouse and human cell models

The proteasome, the system that breaks down proteins, altered the pace of neuronal development in mouse and human cell models

On August 13, in a Developmental Cell paper, researchers compared protein turnover in mouse and human neural progenitors, the cells that develop into neurons. They then altered proteasome activity and observed when the cells moved into the next state.

Neural development proceeds through a sequence of transitions. Some proteins activate the developmental program, while others maintain the previous state. The proteasome breaks down proteins that the cell has marked for removal. In a 2020 study, the same group found that proteins persist longer in human cells. The researchers have now tested whether the rate of protein breakdown affects the timing of cell state transitions.

Across thousands of proteins, the median time required for half of the molecules to disappear was 27,9 hours in human progenitors and 18,2 hours in mouse progenitors. The authors also generated neurons after cell division had ended and again found a difference: about 22,93 hours in human cells compared with 11,45 hours in mouse cells. Thus, the difference in protein turnover persisted after cell division.

Proteasome activity was 1,43 times higher in mouse progenitors. When the researchers reduced this activity with a low dose of an inhibitor, the cells retained early developmental markers for longer, while late markers appeared less often. In human cells, the authors activated PSMB5, a gene that encodes one of the functional components of the proteasome. After 48 hours, proteasome activity had increased. Later, a larger proportion of cells entered a neuronal state, as determined by the presence of TUBB3 protein.

The final experiment examined a transition within a single regulatory circuit. In a mouse cell line, the authors accelerated the degradation of IRX3, a protein that keeps OLIG2 inactive. OLIG2 regulates motor neuron formation. After 18 hours, IRX3 had almost disappeared from the treated cells, and more cells had active OLIG2.

In these cell models, the genetic network determines the sequence of development, while the rate at which its regulatory proteins are removed influences when the next transition occurs.