Huntington’s Chorea was introduced in 1872 and is a fatal somatic dominant inheritanceneurodegenerative disease. It is characterized by progressive extremity irregularities, rapid movements (chorea), mental deterioration, and psychiatric problems such as personality changes. The disorder is caused by a genetic error present at birth, but its symptoms often begin in mid-adulthood. The common age of onset is between 30 and 55 years, but there have been reports of onset starting from 2 years and up to 92 years. Usually the earlier the onset, the more severe the symptoms and the faster the disease progresses. For over a century and a half, there has been a lack of effective drugs to treat or delay the disease.
Scientists at Washington University School of Medicine in St. Louis are trying to understand how the aging process triggers the onset of Huntington’s disease, with the hope that the results could lead to treatments that delay or prevent neurodegeneration.
Improving the neuronal autophagy pathway can slow the progression of Huntington’s disease
Autophagy (autophagy) is a process that involves the cellular structure through the lysosomal mechanism to send damaged organelles or misfolded proteins to lysosomes for degradation and reuse. It can also be considered a cellular self-regeneration process, which is responsible for elimination in the waste.
One of their articles was published in Nature Neuroscience (Neuroscience of nature), new research in the journal shows that as patients age, Huntington’s disease progressively impairs an important cellular cleansing process in autophagy. This cellular cleansing is important in Huntington because the waste products that build up in certain types of neurons can cause those cells to die prematurely. Previous studies have found that autophagy can help human cells repair themselves by improving health by “rebooting” them. Increasing the autophagy pathway in these neurons, which are produced by the skin cells of people with Huntington’s disease, protects the cells from death, the researchers say.
Middle spiny neurons produce problematic mRNA, leading to cell death
Huntington’s disease destroys a specific type of brain cell called middle spiny neurons, the loss of which can lead to involuntary muscle contractions, impaired mental health, and cognitive decline. Patients typically live on average about 20 years after the first signs of the disease appear.
In the study, the researchers reprogrammed the patients’ skin cells into medium-sized spiny neurons using a technique they developed that allows adult skin cells to be converted directly into various types of brain cells, depending on the number of cells in the brain. skin Depends on the amount of exposure to signaling molecules. The technique can also use stem cells, but stem cells reset the cell’s biological clock to an early stage of development, which is not useful when studying diseases that only have symptoms in adulthood.
The study’s senior author, Andrew S. Yoo, Ph.D., a professor of developmental biology at the University of Washington, and his team collected skin cell samples from patients of different ages and patients and modeled the disease before and after symptoms, allowing researchers to differentiate between younger and older patients with Huntington’s disease.
The research team found that medium spiny neurons reprogrammed from the skin cells of elderly patients with symptomatic Huntington’s disease produce very high levels of mRNA, a molecule called miR-29b-3p. This was not observed in reprogrammed neurons in young Huntington’s patients or in healthy individuals of any age. Researchers have shown that mRNA triggers a cascade of events, including impaired autophagy in these cells. As skin cells complete their transformation into neurons, they begin producing the problem mRNA, autophagy slows down, and the cells begin to die. Comparing neurons from different age groups, also converted by Huntington’s skin cells, it emerged that cells from older patients are much rarer, because the aging process impairs autophagy, leading to cell death.
G2 compounds to prevent neuropathy in Huntington’s disease
Lowering the levels of this mRNA allows autophagy to continue and protects neurons from death, the researchers say. Additionally, autophagy was also found to be enhanced with a compound called G2, which protects diseased neurons from death. Protection against cell death also improved as researchers increased the dose of G2.
G2 is derived from a series of structural analogs identified by high-throughput screening of autophagy-enhancing drugs that correct cellular accumulation of mutant alpha-1-antitrypsin Z, resulting in alpha-1-antitrypsin deficiency (deficiency of alpha-1-antitrypsin). liver disease caused by 1-antitrypsin deficiency, ATD). Therefore, G2 compounds are attractive candidates for the prevention of neuropathy in Huntington’s disease, liver disease in alpha-1-antitrypsin deficiency and other cytotoxic effects of abnormal accumulation of misfolded proteins.
The study also revealed tantalizing clues to cognitive decline during normal aging. By comparing symptomatic neurons with presymptomatic neurons and healthy neurons in both young and old, the researchers found that neurons in healthy older adults produced slightly higher levels of harmful microRNAs, but in far lower amounts than symptomatic neurons.
Dr. Yoo said, “By modeling the different stages of the disease throughout life, we can determine how aging affects the onset of the disease and we can begin looking for ways to delay its onset. Our research also shows what triggers the onset of Huntington’s disease. Could be associated with age-related decline in neuronal function. Understanding the causes of aging can help develop new strategies for treating and preventing Huntington’s disease and other neurodegenerative diseases caused by aging “.
References:
- https://www.news-medical.net/news/20221028/Huntingtons-disease-impairs-autophagy-in-older-patients.aspx
- https://medicine.wustl.edu/news/cellular-housekeeping-process-implicated-in-fatal-neurological-disorder/
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