Mitochondria and Huntington's disease
Huntington's disease has been linked to mitochondrial disorders
Scientists hope that their discovery will help create the first cure for this severe genetic disease.
Due to a mutation that is associated with a genetic disease of the nervous system – Huntington's disease – the mitochondria are disrupted. As a result, neurons in the brain self-destruct due to the action of innate immunity. This conclusion was reached by neurophysiologists from the Massachusetts Institute of Technology (MIT), whose article was published by the scientific journal Neuron (Lee et al., Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation).
"The RNA molecules that secrete the affected mitochondria behave like fragments of the viral genome from the point of view of the rest of the cell. Because of this, the innate immunity is activated and the neuron dies. We assume that this process is one of the reasons for the development of inflammation associated with Huntington's disease," she said Miriam Heyman, associate professor at MIT and one of the authors of the paper.
Huntington's disease is a severe, progressive disease of the nervous system, which is associated with the appearance of mutations in the HTT gene. Its exact role in the work of the body is still unknown, but too many genetic repeats will appear inside it, then by about 30-50 years of life, the neurons of the brain begin to die.
First of all, this happens in the so-called striatum of the brain, which is responsible for maintaining muscle tone, decision-making, inhibitory control and many other functions. Due to the death of cells in it, the carrier of Huntington's disease periodically begins to make erratic and involuntary movements, gradually losing control of the muscles. Subsequently, cognitive functions of the brain are also disrupted, but the nature of these failures is individual for each patient.
As Heyman notes, scientists still do not know exactly how nerve cells of the striatum and other areas of the brain die, as well as what role damaged protein molecules play in this process, for the production of which the HTT gene is responsible. This is, in particular, due to the fact that other mammals do not suffer from such a disease, and attempts to reproduce it artificially ended unsuccessfully.
Blocking Huntington's Disease
Neurophysiologists from MIT have taken a big step towards solving all these problems. For the first time, they traced how the appearance of a mutation in HTT affected the work of all other genes and proteins in individual neurons of mice. For these experiments, scientists used samples of brain tissue from people who died from Huntington's disease. The authors of the study tracked the activity of all genes in their cells, comparing the data obtained with what was happening in the brains of rodents.
Experiments have shown that both mutant mouse cells and neurons of Parkinson's disease carriers extracted from their striatum behaved as if they were attacked by viruses. In addition, scientists have recorded serious violations in the activity of genes that are associated with the normal operation of mitochondria – the main cellular power plants.
Subsequent observations showed that both of these disorders are directly related. If mutations appeared in HTT, then oxidative processes were disrupted inside the mitochondria, which caused them to release a large number of strands of RNA copies of their own genome into the environment.
These molecules, in turn, were recognized by protein kinase R (PKR), one of the proteins of the innate immune system. It protects the body from infections by connecting with viral RNA molecules and triggering a chain of reactions that eventually cause the infected cell to self-destruct.
On the right are neurons of a mouse model of Huntington's disease containing much more PKR (green) than the neurons on the left obtained from a healthy mouse – VM.
Similar processes, as shown by experiments on mice, begin to occur in the brain cells of carriers of Huntington's disease even before all other disorders appear.
Interestingly, similar disorders in the work of innate immunity, which are accompanied by the appearance of inflammation in the brain, occur in some other diseases of the striatum, such as Ecardi – Gutierrez syndrome or thiamine deficiency. They arise due to mutations in other genes, but also lead to the mass death of neurons under the action of the PKR protein.
The study of these diseases, scientists hope, will help create the first effective drugs for Huntington's disease, which could suppress the activity of protein kinase R in the brain cells of patients, but would not disrupt the work of this important protein of the immune system in other organs of the body.
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