Autophagy against neurodegeneration
Stimulation of autophagy can protect against Huntington's disease
Luka Kormiltsev, PCR.news
Huntington's disease is a deadly genetic neurodegenerative disease that manifests itself with age. Due to the gradual destruction of the most sensitive parts of the brain to the disease, problems with movement control appear and increase in the carrier, and then with behavior and thinking. The mechanisms that link the onset of the disease with aging have been little studied to date. Researchers from the Washington University School of Medicine in St. Louis have found out which features of gene regulation affect variations in the disease picture in people of the same age and with a similar genetic status.
Neurons transformed from skin cells of a young patient with presymptomatic Huntington's disease are shown on the left. On the right are neurons transformed from skin cells of an elderly patient with symptoms; autophagy is disrupted in them, which leads to cell death.
The cause of Huntington's disease is a mutation in the huntingtin protein gene (hereinafter HTT) and the subsequent accumulation of a defective form of protein in the most vulnerable subtypes of neurons. HTT becomes toxic due to an increase in the number of repeats of the CAG codon in the polyglutamine tract. Up to 36 glutamine residues in a row are safe, but then the probability of the disease begins to grow: the more repetitions, the earlier the symptoms will appear.
The number of repetitions is not the only factor affecting the rate of development of the disease. Most patients have 40-50 repetitions, and the first symptoms occur in 35-45 years, while the picture of the course of the disease can vary greatly. The aim of the new study was to search for other age-related internal causes of the disease and suggest possible therapies.
The scientists took fibroblasts from four groups of donors of different ages: carriers of Huntington's disease with symptoms, asymptomatic carriers and two healthy control groups, one young, the other elderly. With the help of miR-9/9* and miR-124 neuronal microRNAs, fibroblasts were reprogrammed into projection spike neurons (MSN) of the striatum, a subtype of neurons most vulnerable to mutant HTT. This method of obtaining the necessary neurons, in contrast to the use of stem cells, made it possible to preserve epigenetic information about aging. The preservation of information is confirmed by the fact that neurons from patients with symptoms died significantly more often than those obtained from still healthy carriers, although both groups of neurons synthesized mutant HTT.
To identify the features contributing to resistance to pathogenic HTT, a transcript of each group of neurons was obtained immediately after the completion of cell reprogramming. The genes were divided into modules, and then functional groups of genes were isolated within each module. Thus, the module was determined, the transcription changes in which are most likely associated with the phenotype of neurons susceptible to degeneration. It contained genes associated with apoptosis, autophagy, and protein folding. After that, the availability of chromatin for transcription was evaluated and differences associated with the development of symptoms in patients were identified. Regulatory sequences were analyzed in candidate genes.
As a result, a key interaction for the study was determined — suppression of the expression of the STAT3 protein gene involved in the regulation of autophagy by an excess of miR-29b-3p microRNA, which bound to its 3’-untranslated site.
By chemical stimulation of autophagy, inhibition of miR-29b-3p and overexpression of STAT3, the authors confirmed that this interaction makes an important contribution to the severity of neurodegenerative processes in patients of the same age: all three interventions reduced the death of neurons in culture.
Interestingly, this is a unique interaction for humans, which has not been confirmed for mice, from which the authors conclude that it is important to model hereditary diseases on human cells.
Before some age, the defective form of HTT, prone to aggregation, is removed from the cell due to autophagy of protein clots. In humans, increasing STAT3 deficiency leads to a change in the transcriptome and subsequent weakening of autophagy processes, which causes HTT accumulation and cell death.
The shown association with a drop in STAT3 expression opens up new avenues for research into the treatment of Huntington's disease. In recent years, several potential drugs have already been rejected for one reason or another and have not entered the market, so a new direction may be promising.
In addition, Huntington's disease is a vivid example of a disease associated with aging, so the study of its epigenetics contributes to the study of aging as a whole as an epigenetic phenomenon.
Article by Oh et al. Age-related Huntington's disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights enhanced autophagy is published in the journal Nature Neuroscience.
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