A new mechanism for balancing protein stability during neuronal development

A new mechanism for balancing protein stability during neuronal development

A research team recently discovered an unexpected role of the heat shock proteins (HSPs), also known as the molecular chaperones, during neuronal differentiation, which refers to the process a neuron takes to acquire its shape and function. HSPs are mostly known to protect cells from various stresses, e.g. extreme temperatures, toxins, and mechanical damage, and to safeguard tissue development. This new study, however, suggests that the Hsps can also play an inhibitory role in neuronal differentiation by destabilizing the cytoskeleton of the neurons. The research findings were recently published in a leading journal in the developmental biology - Development.

Protein quality control is important for normal development in human cells, and its dysregulation leads to a range of neurodevelopmental disorders. Inside cells, the Hsps and other chaperones promote protein folding and stability, while the ubiquitination-proteasome system (UPS) targets proteins for degradation. The HSPs and UPS pathways often collaborate to eliminate irreparable proteins in some cellular contexts, but their interaction in developing neurons is not well understood.

Using neurons from a model organism called Caenorhabditis elegans, which can be easily genetically manipulated, the research team discovered that when the UPS system is compromised in genetic mutants, a major part of the cytoskeleton called microtubules is destabilized, leading to defects in the axonal growth (axons are the projections of neurons). Surprisingly, through a genetic screen, the team found that deleting the HSPs and co-chaperones can fully rescue the defects caused by the compromised UPS, suggesting that the two systems counter each other during development.

Furthermore, a protein kinase called DLK-1 was found to be stabilized by the HSPs and degraded by the UPS. The overabundance of DLK-1 caused instable microtubules and neuronal growth defects. Thus, by regulating the same target proteins, HSPs and UPS can fine-tune the level of critical signaling molecules and create a tightly controlled balance between protein stability and degradation. The discovery of this mechanisms can help understand the molecular basis of neurodevelopmental diseases, nerve regeneration, and neurodegenerative diseases.

"This research identifies a previously underappreciated role of HSPs in neuronal development and suggests that HSPs may not be always protective of cellular morphology and functions," said the senior author. At the same time, this research also opens up a new direction to understand the antagonism between the HSPs and the UPS system in maintaining a balance between protein stabilization and turnover.