Messy RNA can't stop the "dance step"

misplaced RNA in the brain can destroy neurons, make it impossible for people to control their movements, and even have Huntington's disease.
neuroscientists at the Massachusetts Institute of Technology have found that the main cause of neuron death in Huntington's disease patients may be an immune response to genetic material released abnormally by mitochondrials. Mitochondrials are the cellular components that provide energy.
study looked at different types of brain cells and how to respond to mutations that cause Huntington's disease. The researchers measured differences in brain samples from normal people in brain samples of hunting deaths in different cell types at different stages of disease development, as well as RNA levels in mice modified with varying degrees of genetic mutations. The paper was published recently in Neurons.
RNA released by the mitochondrials looks like viral RNA, which triggers innate immunity and can lead to cell death. Myriam Heiman, co-author of the study and an associate professor in the Department of Brain and Cognitive Sciences at the Massachusetts Institute of Technology in the United States, said, "We believe this is part of the path of triggering inflammatory signaling." Huntington disease is a degenerative brain disease caused by chromosomal explicit genetics that ruthlessly robs victims of control over movement and thought. Patients may develop dance symptoms such as twitching and may eventually die prematurely. Globally, 3 to 10 people per 100,000 people are affected by the disease and there is currently no cure.
the disease was named after American physician George Huntington, who described it in 1872. Scientists have been exploring the disease for more than 100 years. In 1993, scientists discovered that the genetic mutation that caused Huntington's disease was located near the top of chromosome 4's short arm. But no one knows how the mutant Huntington's protein (mHTT) destroys neurons.
even Huntington's disease is a late-stage neurodegenerative disease, but neuroimaging studies in mice and pre-symptom mutant carriers have shown that Huntington's disease may affect neurodevelopment.
The study, published July 16 in Science, found that tissue in human fetuses (13 weeks pregnant) carrying a mutation in Huntington's disease showed significant abnormalities in the developmental cortical cortical, including misalposition of the mutated Huntington's protein and the connecting complex protein, defects in neurogenic cell polarization and differentiation, abnormal filamentation, and changes in filamentation and cell cycle processes.
the researchers say Huntington's disease has an effect on neurodevelopment, not just a degenerative disease.
, however, "because the function of mutant proteins and the mechanisms associated with causing disease are still unknown, traditional methods cannot be used to screen blockers for their pathological functions." Lu Boxuan, a researcher at Fudan University's National Key Laboratory of Medical Neurobiology, said.to better explore the secrets of Huntington's disease, the Heiman team used two different screening techniques, TRAP for mouse models, and single-core RNA sequencing for mice and people.
surprising finding is that RNA in mitochondrials is mistakenly placed in brain cells called hedgehog-casting neurons (SPNs), destroying them and causing fatal neurological symptoms. The researchers observed that these free RNA appeared to be different in cells than RNA extracted from the nuclei of the cells, triggering a problematic immune response.
, they not only found the presence of mitochondrial RNA, but also showed a lack of gene expression in the phosphate process, a process in which fuel-needed neurons produce energy.
, mouse experiments showed that this reduction in phosphate oxide and an increase in mitochondrial RNA release occurred in the early stages of Huntington's disease, before most other gene expression differences emerged.
, the researchers also found an increase in the expression of an immune system protein called PKR, which has been shown to be a sensor for releasing mitochondrial RNA. In fact, the team found that PKR not only rises in neurons, but is also activated and binds to mitochondrial RNA.
, said the new findings appear to be consistent with some clinical symptoms. Huntington's disease, for example, can cause damage to symposome regions of the brain; in Aicardi-Goutières syndrome, the same brain region can be damaged due to congenital immune response disorders; and children with thiamine deficiency develop mitochondrial dysfunction, which studies have shown in mouse models that also exhibit PKR activation.
" the paper's biggest highlight is the histology section, which should be the first histological study using single-cell (single-core) sequencing and TRAP (measuring mRNA being translated). Lu, who was not involved in the study, told China Science Daily.Heiman said they also found significant differences in gene expression, including those related to important neural functions, such as synhap circuit connections and biological clock functions.
addition, the team found that the main regulatory factor for these gene transcription changes in neurons may be the responsic acid lime b transcription factor. "This may be a clinically useful finding because there are drugs that activate Rarb." "If we can suppress transcription disorders, we can change the outcome of the disease," Heiman told China Science. But this is an important assumption that needs to be validated. On
other hand, many of the gene expression differences the researchers saw in neurons in human brain samples were very much in line with the changes they saw in mouse neurons, further ensuring that mouse models were useful for studying the disease. The problem has been plaguing the field, as mice don't usually die as many neurons as people do.
"We see that mouse models actually reproduce well the changes in gene expression of neurons that occur during hunting disorders in humans. But other non-neuron cell types do not show as much conservatism between human diseases and mouse models, and we believe this information will help other researchers conduct future research. Heiman said.
, in addition to mouse models, pigs are also "working" in the field. In 2018, researchers used gene editing technology CRISPR-Cas9 and sophylactic cell nuclear transplantation for the first time to successfully develop the world's first Huntington's disease gene knock into pigs, accurately simulating human neurodegenerative diseases.
In addition, in 2019, the Ruberian team pioneered the original concept of drug development based on autophagy small binding compounds, and cleverly discovered small molecular compounds specifically reducing Huntington's disease-pathogenic proteins through screening based on compound chips and cutting-edge optical methods, promising to bring new light to clinical treatment.
related paper information: