Cellular housekeeping process implicated in fatal neurological disorder | Washington University School of Medicine in St. Louis

Huntington’s disease, a fatal inherited neurodegenerative disease, is caused by a genetic error present at birth, although its symptoms often do not appear until middle adulthood. Scientists at Washington University School of Medicine in St. Louis have been trying to understand how the aging process triggers the onset of symptoms, hoping that this knowledge could point to treatments that delay or prevent neurodegeneration .

To that end, a new study from the University of Washington indicates that as patients age, the disease progressively impairs an important cellular maintenance process called autophagy, which is responsible for removing waste from cells. This housekeeping is important in Huntington’s disease because an accumulation of waste in a specific type of neuron leads to the premature death of these cells.

The researchers also showed that enhancing the autophagy pathway in these neurons that were created from the skin cells of Huntington’s patients protects these cells from death.

“Our study reveals how aging triggers a loss of the crucial process of autophagy – and indicates how we might try to restore this important function, with the aim of delaying or even preventing Huntington’s disease,” said the author. principal Andrew S. Yoo, PhD. , professor of developmental biology at the University of Washington.

The study, published Oct. 27 in the journal Nature Neuroscience, may also offer clues to understanding cognitive decline in aging in general.

Huntington’s disease destroys a specific type of brain cell called medium spiny neurons, the loss of which causes involuntary muscle movements, impaired mental health and cognitive decline. Patients typically live about 20 years after the first signs of the disease appear.

For this study, the researchers reprogrammed the patients’ skin cells into medium spiny neurons using a technique they developed that directly transforms adult skin cells into different types of brain cells, depending on the specific recipe of signaling molecules to which skin cells are exposed. More common techniques involve the use of stem cells – but stem cells reset the biological clocks of cells to an early developmental state, which is not useful when studying diseases that only become symptomatic at adulthood.

“We collected skin cell samples from different patients of different ages and modeled the disease before and after the development of symptoms, which allowed us to identify differences between younger and older patients with Alzheimer’s disease. Huntington,” Yoo said. “We knew there had to be changes as patients got older. They all have a genetic mutation in the huntingtin gene. We wanted to find the difference between young patients who show no symptoms and older patients who actively show signs of the disease.

Yoo and his colleagues, including co-first authors Youngmi Oh, PhD, and Seongwon Lee, PhD, both scientists in Yoo’s lab, found that reprogrammed medium spiny neurons from skin cells of elderly patients with Symptomatic Huntington’s disease produced very high levels of a microRNA molecule called miR-29b-3p. These elevated levels were not observed in reprogrammed neurons from younger patients with Huntington’s or in reprogrammed neurons from healthy individuals of any age. The researchers showed that the microRNA triggered a chain of events that included impaired autophagy in these cells. When the skin cells finished converting into neurons, they started producing the problematic microRNA, autophagy slowed down, and the cells started dying.

The researchers then showed that reducing levels of this microRNA allowed autophagy to continue and protected neurons from death. Additionally, they found that enhancing autophagy with a chemical compound called G2 protected diseased neurons from dying. As the researchers increased the dose of G2, protection against cell death also improved.

G2 is derived from a series of analogs that were discovered in the labs of co-authors David Perlmutter, MD, Executive Vice Chancellor for Medical Affairs, George and Carol Bauer Dean of the School of Medicine, and Spencer T. and Ann W Professor Emeritus Olin; Gary Silverman, MD, PhD, Harriet B. Spoehrer Professor and Chief of the Department of Pediatrics; and Stephen C. Pak, PhD, professor of pediatrics in the Division of Neonatal Medicine. G2 has been identified by high-throughput screening for autophagy-activating drugs that may correct cellular accumulation of the alpha-1-antitrypsin Z variant that causes liver disease in alpha-1-antitrypsin deficiency (ATD ). G2 compounds could therefore represent attractive candidates for preventing neurodegeneration in Huntington’s disease, liver disease in alpha-1-antitrypsin deficiency, and possibly other diseases in which aberrant accumulation of misfolded proteins is toxic to cells.

The study also revealed what could be a tantalizing clue to understanding cognitive decline in normal aging. By comparing symptomatic neurons to pre-symptomatic neurons and healthy neurons from young and older adults, the researchers found that neurons from healthy older adults produced slightly elevated levels of harmful microRNA, but in much lower amounts. than symptomatic adult neurons. Patients with Huntington’s disease. The study suggests that even in normal, healthy aging, medium spiny neurons gradually produce low levels of this microRNA, which may interfere with healthy cellular maintenance of autophagy.

“By modeling the different stages of disease across the lifespan, we can identify how aging plays a role in disease onset,” Yoo said. “With this information, we can start looking for ways to delay this onset. Our study also suggests that the molecule triggering the onset of Huntington’s disease may play some role in the decline of neuronal function associated with age in general. Understanding the component of aging that triggers neurodegeneration can help develop new treatment and prevention strategies for Huntington’s disease and other neurodegenerative conditions that develop in later life.

Yoo and his team are also working with other collaborators using their cell reprogramming technique to study forms of Alzheimer’s disease, tauopathy and other neurodegenerative conditions.