Two birds with one stone with one inhibitor
Neurodegenerative conditions are characterized by damage to axons – long thin processes that conduct electrical impulses from one nerve cell to another, providing cellular communication. Axon damage often leads to neuronal damage and cell death.
It is known that inhibition of the enzyme dual leucine zipper kinase, DLK (double leucine lightning kinase) protects neurons in models of neurodegenerative diseases, but this enzyme also plays an important role in ensuring the growth of axons. Consequently, inhibition of DLK as a therapeutic approach in neurodegenerative diseases is limited to neuroprotective effect without axon regeneration and does not lead to restoration of lost functions.
A group of researchers from the University of California San Diego School of Medicine and the Sheely Institute of Vision at the University of California, San Diego has identified another family of enzymes whose inhibition has a powerful neuroprotective effect, as well as accelerates axon regeneration.
The search for the chemical compounds involved was carried out in two stages. To do this, the researchers created retinal ganglion cells from adult human stem cells. Ganglion cells are located near the inner surface of the retina of the eye. They receive visual information from photoreceptors and help transmit it to the brain. First, groups of chemicals were tested to assess their ability to increase the survival of ganglion cells, and then to measure the ability to stimulate regeneration.
The researchers found that the GCK-IV kinase family of enzymes (germ cell kinase IV kinases) is optimally suited as a target: their inhibition led to maximum neuroprotection while stimulating axon regeneration. This makes disabling GCK-IV kinases an attractive therapeutic approach for a number of neurodegenerative diseases.
Using adeno-associated vectors (AAV) in combination with genome editing, the researchers confirmed that knockout of the GCK-IV kinase gene increases the survival of neurons comparable to knockout of the DLK gene, while promoting axon regeneration.
Retinal ganglion cells were used in the study, since glaucoma is one of the most common neurodegenerative diseases. Increased intraocular pressure is accompanied by progressive death of retinal ganglion cells and their axons, leading to structural and functional damage to the optic nerve, visual impairment and irreversible blindness. Glaucoma is the second (after wet macular degeneration) leading cause of blindness worldwide.
The authors noted that it is not yet known whether the results obtained can be transferred to other types of neurons.
Article by A.K.Patel et al. Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons is published in the journal PNAS.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru Based on the materials of the UC San Diego News Center: Researchers Discover A Clue to How to Protect Neurons and Encourage Their Growth.