Novel Gene Regulates Axon Regeneration in the Central Nervous System

A scientific investigation led by researchers at HKUST has uncovered promising new avenues for treating central nervous system (CNS) injuries, with findings published in the Proceedings of the National Academy of Sciences. The study identified a previously unknown gene that controls the regrowth of various CNS axon types, marking a significant advancement in neural repair research.

Repairing the CNS remains a major medical challenge in adult mammals, particularly in cases of spinal cord injury, which often result in permanent loss of function. A team led by Professor Kai Liu at the HKUST Division of Life Science found that the enzyme lipin1 plays a crucial role in axon regeneration through its impact on neuronal lipid metabolism. These findings, published in Neuron, highlight the importance of lipid regulation in neural repair.

Suppressing lipin1 in retinal ganglion cells triggered a metabolic shift from storage lipids toward phospholipids, producing key signaling molecules, including phosphatidic acid (PA) and lysophosphatidic acid (LPA). These molecules activated the mTOR pathway, a critical regulator of cellular growth and maintenance.

While this discovery sheds light on axon regeneration, further research is needed to fully understand the complex mechanisms involved and their potential for treating spinal cord injuries.

Professor Liu’s team developed a unique shRNA targeting lipin1 mRNA expression, which they delivered to neuronal cells using an AAV vector system, achieving a 63% reduction in lipin1 expression.

Their experiments showed that when lipin1 was suppressed, PA and LPA levels increased, enhancing the activity of the mTOR and STAT3 signaling pathways. This molecular shift improved nerve regeneration capacity, indicating that axon regrowth is regulated by an inhibitory feedback mechanism involving lipin1, PA/LPA, and mTOR.

Spinal cord injuries remain difficult to treat, with few effective options. While earlier research demonstrated that targeting Pten can promote nerve fiber regrowth, its role in cancer makes it unsuitable for therapeutic use, prompting the search for alternative strategies.

One critical neural pathway, the corticospinal tract, connects the cerebral cortex to the spinal cord and controls precise motor functions. In a study using complete spinal cord transection, researchers found that reducing lipin1 expression significantly enhanced nerve fiber regeneration in this pathway.

The regenerative effects of reducing lipin1 were comparable to those of removing Pten. Furthermore, reducing lipin1 levels promoted regeneration in ascending sensory nerve fibers, suggesting broader therapeutic potential.

The study demonstrates that suppressing lipin1 affects neuronal fat metabolism while activating the mTOR and STAT3 pathways via PA and LPA, thereby enhancing CNS axon regeneration.

These findings position lipin1 as a key regulator of axonal regeneration, offering a potential therapeutic target for treating spinal cord injuries.