A new screening assay has identified small molecules capable of protecting brain mitochondria from stress conditions that commonly occur in Alzheimer’s and other neurodegenerative diseases.
These preclinical results in mice support the therapeutic potential of these newly discovered compounds.
The study, “Neuron-based high-content assay and screen for CNS active mitotherapeutics,”was published in Science Advances.
Mitochondria, the organelles that provide energy to cells, are critical for cellular health and survival, especially for nerve cells (neurons).
Impairments in mitochondria dynamics and function are a hallmark of several neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS). Therapies that protect and enhance mitochondrial function are thus a potential strategy to prevent the neurodegeneration associated with these diseases.
“It hasn’t yet been emphasized in the search for effective therapeutics, but mitochondrial failure is a feature of many neurodegenerative disorders and something that must be corrected if neurons are to survive,” Ronald Davis, neuroscience professor at Scripps Research and the study’s lead author, said in a press release.
“So I’m a big believer that finding mitochondria-protecting molecules is the way to go against these diseases,” he added.
Previous studies have tried to identify molecules that boost mitochondrial function using model organisms (such as yeast), and immortalized (capable of reproducing indefinitely) non-neuronal human cells. However, these studies have not used mature neurons, since these cells are hard to work with in the lab because they do not divide to produce new neurons.
Given the unique biology and architecture of neurons, “cell-based screens that use neurons are predicted to be more successful in identifying potential mitotherapeutics [mitchondria-targeting] for brain disorders compared to traditional screens using immortalized, non-neuronal cell lines,” the researchers wrote.
In the new study, these researchers developed a screening system to identify compounds that could target and protect mitochondria inside neurons. For this, they used mature neurons grown in a laboratory dish that were modified to carry mitochondria labelled with fluorescent tags. Using microscopy, the researchers were then able to analyze changes in the number, shape, and health (measured using the circularity) of mitochondria after the neurons were exposed to different compounds.
In a first screen, the team tested a library of 2,400 compounds out of which 149 had a significant positive effect in mitochondrial number, shape, and health. In a second test, they narrowed the first candidates to 67 compounds that act as modulators of neuronal mitostasis, or MnMs. Mitostasis is the combination of processes that help maintain an adequate number of healthy mitochondria in neurons across their lifetime.
Out of the 67 compounds, “32 increased elongation, 45 increased mitochondrial content, and 33 increased mitochondria health.” Thirty-five affected more than one of these parameters.
Sixty-one of the 67 MnMs increased the function of mitochondria, measured using either the generation of ATP (a key energy-providing molecule), or the charge across the mitochondria’s inner membrane (which reflects mitochondrial activity).
Of note, none of the MnMs had been previously identified in other screens with different types of cells.
Twelve of these MnMs were then selected for further testing. Several were shown to protect the mitochondria in neurons from different stresses known to cause damage in Alzheimer’s disease. These included peroxide (a very reactive molecule that can further harm other mitochondria when it’s released from damaged mitochondria), excess glutamate (a molecule used in nerve communication that can damage neurons in high levels), and toxic clusters of the amyloid-beta protein — a hallmark of Alzheimer’s disease.
The researchers then added these MnMs to isolated mitochondria to identify which ones directly targeted mitochondria to protect them from these stresses.
Dyclonine, an anesthetic found in some products to relieve sore throat, was identified as the best MnM to protect mitochondria. Dyclonine protected neurons against glutamate and peroxide stresses, and increased the activity of neuronal synapses — the junction between two nerve cells that allows them to communicate.
Furthermore, energy production was increased in mitochondria isolated from healthy mice treated with dyclonine, indicating that the molecule also works in vivo.
“It remains a mystery why dyclonine and other local anesthetics have such effects on mitochondria in neurons — we certainly didn’t anticipate this,” Davis said.
“But the compounds we identified give us strong hope that we’ll see beneficial effects when we test them in animal models of specific neurodegenerative diseases, as we’re now doing,” he added.
The researchers are testing the selected MnMs in animal models of Alzheimer’s, ALS, and other diseases. They hope to identify their exact targets and determine their efficacy in treating these neurodegenerative disorders.
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