Although its symptoms frequently don’t appear until middle adulthood, Huntington’s disease is a deadly, inherited neurological ailment that is caused by a genetic defect present at birth. Researchers at the Washington University School of Medicine in St. Louis have been trying to figure out how aging causes symptoms to show up. They want to know this so that they can make therapies that can delay or stop neurodegeneration.
To that end, a recent study from Washington University suggests that the illness steadily deteriorates an essential cellular housekeeping procedure called autophagy, which is in charge of removing trash from cells as patients age. This housekeeping is important in Huntington’s because an accumulation of trash in a certain type of neuron causes such cells to pass away prematurely.
The researchers also demonstrated that protecting such neurons made from Huntington’s disease patients’ skin cells from senescence involves increasing the autophagy process in those cells.
According to senior author Andrew S. Yoo, PhD, a professor of developmental biology at Washington University, “Our study reveals how aging triggers a loss of the crucial process of autophagy—and hints at how we might try to restore this important function, with the aim of delaying or even preventing Huntington’s disease.”
The research, which was published in the journal Nature Neuroscience on October 27, may also help us learn more about how aging causes cognitive problems in general.
Medium spiny neurons, a particular class of brain cells that are destroyed by Huntington’s disease, are responsible for involuntary motor movements, diminished mental health, and cognitive decline. Patients typically live for about 20 years after the initial illness symptoms appear.
In this study, the researchers used a method they created that enables adult skin cells to be directly transformed into different types of brain cells depending on the precise recipe of signaling molecules to which the skin cells are exposed. They reprogrammed patients’ skin cells into medium-sized spiny neurons. Stem cells are used in more widespread approaches, but they reset the biological clocks of the cells to an early embryonic state, making them useless for researching disorders that only manifest in adulthood.
According to Yoo, our modeling of the disease before and after symptoms appeared and the collection of skin cell samples from many patients at various ages allowed us to distinguish between younger and older patients with Huntington’s disease. “We were aware that as patients age, there must be certain changes. The Huntingtin gene has been genetically altered in each of them. We sought to distinguish between young patients with no symptoms and older patients with active illness symptoms. ”
Yoo and his team discovered that medium-spiny neurons reprogrammed from skin cells of elderly patients with symptomatic Huntington’s disease produced extremely high levels of a microRNA molecule called miR-29b-3p. Co-first authors Youngmi Oh, PhD, and Seongwon Lee, PhD, are both staff scientists in Yoo’s lab. Reprogrammed neurons from older Huntington’s patients or from reprogrammed neurons from healthy people of any age did not exhibit these high levels. The researchers demonstrated that the microRNA triggered a series of events in these cells that impaired autophagy. After completing the transition into neurons, the skin cells started to produce the harmful microRNA, autophagy slowed down, and the cells started to die.
The scientists went on to demonstrate that lowering levels of this microRNA let autophagy carry on and guarded the neurons from degeneration. They also discovered that increasing autophagy with the drug G2 prevented the damaged neurons from dying. The protection against cell death was enhanced as the researchers increased the dose of G2.
G2 is derived from a number of analogs that were found in the labs of co-authors Gary Silverman, MD, PhD, the Harriet B. Spoehrer Professor and head of the Department of Pediatrics, Stephen C. Pak, PhD, a professor of pediatrics in the Division of Newborn Medicine, and David Perlmutter, MD, the Spencer T. and Ann W. Olin Distinguished Professor and executive vice chancellor for medical affairs. High throughput screening for autophagy enhancer medications that may stop the cellular housekeeping buildup of mutant alpha-1-antitrypsin Z, which results in liver damage in alpha-1-antitrypsin deficiency, led to the discovery of G2 (ATD). So, the G2 compounds might be good candidates for treating diseases like Huntington’s disease, liver disease caused by alpha-1-antitrypsin deficiency, and maybe even other conditions where an abnormal buildup of misfolded proteins is harmful to cells.
Additionally, the cellular housekeeping study revealed something that might be a fascinating hint for understanding cognitive impairment in typical aging. The neurons of healthy older adults produced slightly elevated levels of the harmful microRNA, but in much smaller amounts than the neurons of symptomatic Huntington’s disease patients. This was observed when the researchers compared the symptomatic neurons to pre-symptomatic neurons and to healthy neurons from both young and older adults. According to the study, medium spiny neurons make less and less of this microRNA as they age normally and healthily. This may stop autophagy from doing its job of keeping cells clean.
According to Yoo, we can determine how aging affects the beginning of the disease by modeling various disease stages over the life span. “With that knowledge, we can start looking for strategies to postpone its commencement. Our research also raises the possibility that the chemical that sets off Huntington’s disease may contribute in some way to the general loss in neuronal function that comes with aging. Huntington’s disease and other neurodegenerative disorders that appear in older people may be treated and prevented using novel treatments that are developed as we learn more about the aspect of aging that triggers neurodegeneration. ”
Using their cellular housekeeping reprogramming method, Yoo and his team are collaborating with additional researchers to look at different Alzheimer’s disease, tauopathy, and neurodegenerative disease forms.
