Summary: Kinase enzymes are essential for neurons to perform autophagy. Researchers found that deleting genes that code for NDR1 and NDR2 kinases impairs neuron health and stimulates neurodegeneration in young and old mice.
Source: Francis Crick Institute
Scientists at the Francis Crick Institute have found that deletion of two genes that code for key enzyme proteins (NDR1 and NDR2 kinases), impairs neuron health and leads to neurodegeneration in young mice as well as adults.
Their study of mouse neurons highlights the essential role of these proteins in maintaining brain health and preventing disease, a finding that could aid in the discovery of future treatments for neurodegenerative diseases such as Parkinson’s disease. and amyotrophic lateral sclerosis (ALS).
As part of their work published in Life Sciences Alliance on November 29, researchers set out to understand the role of kinase enzymes in the development of the nervous system and the maintenance of healthy neurons. For the first time in mice, they deleted the genes that code for NDR1 and NDR2 kinases in neurons.
They found that removing either enzyme alone had no effect on neuronal health, but when both were removed simultaneously, the loss caused neurodegeneration.
In order to understand why neurodegeneration occurs in the absence of these enzymes, the team analyzed brain tissue in more detail and discovered an accumulation of protein clusters marked for elimination, a key feature of many neurodegenerative diseases. This suggests that kinase enzymes are essential for neurons to perform autophagy, the process of removing old or damaged components.
“The neuron’s ability to eliminate toxic proteins is a key defense against neurodegeneration,” says Sila Utanir, head of Crick’s Kinases and Brain Development lab.
“It is important to understand that NDR1 and NDR2 kinases are essential for autophagy, because if there was a way to stimulate their activity with future drugs, it could help eliminate the protein buildup associated with the disease. “
The team also looked in even more detail at the mechanisms involved in the loss of these key enzymes. They discovered that ATG9A, a protein present in certain cell membranes, which is associated with autophagy and lipid recycling, was misplaced and therefore could not function properly.
Flavia Roșianu, first author of the paper, said: “The complex signals sent between our brain cells are all part of a larger picture of neural health.
“In order to understand how our brain develops and why disease occurs, we need to piece together these connections and identify the most important proteins and signals.”
About this genetics and neuroscience research news
Author: Press office
Source: Francis Crick Institute
Contact: Press service – Francis Crick Institute
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Original research: Free access.
“Loss of NDR1/2 kinases impairs endomembrane trafficking and autophagy leading to neurodegeneration” by Flavia Roşianu et al. Life Sciences Alliance
Loss of NDR1/2 kinases impairs endomembrane trafficking and autophagy leading to neurodegeneration
Autophagy is essential for neuronal development and its dysregulation contributes to neurodegenerative diseases. NDR1 and NDR2 are highly conserved kinases involved in neuronal development, mitochondrial health, and autophagy, but how they affect mammalian brain development in vivo is not known.
Single and double use No. 1/2 knockout mouse models, we show that only the double loss of No. 1/2 in neurons causes neurodegeneration. This phenotype was present when NDR kinases were suppressed both during embryonic development, as well as in adult mice.
Proteomics and phosphoproteomics comparisons between No. 1/2 knockout and control brains revealed novel kinase substrates and indicated that endocytosis is significantly affected in the absence of NDR1/2.
We validated the endocytic protein Raph1/Lpd1, as a new NDR1/2 substrate, and showed that NDR1/2 and Raph1 are essential for endocytosis and membrane recycling. In NDR1/2 knockout brains, we observed a significant accumulation of transferrin receptor, p62 and ubiquitinated proteins, indicating a major alteration in protein homeostasis.
Additionally, levels of LC3-positive autophagosomes were reduced in knockout neurons, implying that reduced autophagy efficiency induces p62 accumulation and neurotoxicity.
Mechanically, pronounced mislocalization of the transmembrane autophagy protein ATG9A to the neuronal periphery, impaired axonal trafficking of ATG9A, and increased surface levels of ATG9A further confirm membrane trafficking defects and may underlie the impairment of autophagy.
We provide new insight into the roles of NDR1/2 kinases in maintaining neuronal health.
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