Huntington's disease impairs autophagy in elderly patients

Huntington's disease impairs autophagy in elderly patients

Huntington's disease, a fatal, inherited neurodegenerative disorder, is caused by a genetic defect that is present at birth, although its symptoms often do not begin 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, with the expectation that this knowledge could point to treatments that delay or prevent neurodegeneration.

To that end, a new study from Washington University shows that as patients age, the disease gradually impairs an important cellular housekeeping process called autophagy, which is responsible for clearing waste from cells. This housekeeping is important in Huntington's disease because a buildup of waste in a certain type of neuron leads to the premature death of such cells.

The researchers also showed that enhancing the autophagy pathway in such neurons created from skin cells of HD patients protected these cells from dying.

Our study shows how aging triggers a loss of the crucial process of autophagy – and provides clues as to how we might try to restore this important function, with the aim of delaying or even preventing HD.”

Andrew S. Yoo, PhD, senior author, professor of developmental biology, Washington University

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

Huntington's disease destroys a specific type of brain cells 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, researchers reprogrammed patients' skin cells into medium-sized spiny neurons using a technique they developed that allows adult skin cells to be converted directly into different types of brain cells, depending on the specific recipe of signaling molecules to which the skin cells are exposed. More common techniques involve the use of stem cells – but stem cells reset cells' biological clocks to an early developmental state, which is not useful when studying diseases that do not become symptomatic until adulthood.

"We collected skin cell samples from different patients of different ages and modeled the disease before and after symptoms developed, which allowed us to identify the differences between younger and older patients with Huntington's disease," Yoo said. "We knew that there must be changes as patients get older. They all have a genetic mutation in the huntingtin gene. We wanted to find the difference between young patients without symptoms and older patients who are actively showing signs of the disease."

Yoo and his colleagues, including co-first authors Youngmi Oh, PhD, and Seongwon Lee, PhD, both research associates in Yoo's lab, found that medium-sized spiny neurons reprogrammed from skin cells of older patients with symptomatic Huntington's disease produced very high levels of a microRNA molecule called miR-29b-3p. These high levels were not observed in reprogrammed neurons from younger HD patients or in reprogrammed neurons from healthy individuals of any age. The researchers showed that the microRNA triggered a chain of events that included impairment of autophagy in these cells. When the skin cells finished converting into neurons, they began producing the problematic microRNA, autophagy slowed, and the cells began to die.

The researchers went on to show that reducing the levels of this microRNA allowed autophagy to continue and protected the neurons from dying. In addition, they found that enhancing autophagy with a chemical compound called G2 protected the diseased neurons from death. When the researchers increased the dose of G2, protection against cell death also improved.

G2 is derived from a series of analogs discovered in the laboratories of co-authors David Perlmutter, MD, executive vice chancellor for medical affairs, the George and Carol Bauer Dean of the School of Medicine, and the Spencer T. and Ann W. Olin Distinguished Professor; 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 was identified through high-throughput screening for autophagy enhancer drugs that could correct the cellular accumulation of the variant alpha-1-antitrypsin Z, which causes liver disease in alpha-1-antitrypsin deficiency (ATD). The G2 compounds could therefore represent attractive candidates for preventing neurodegeneration in Huntington's disease, alpha-1-antitrypsin deficiency liver disease, and possibly other diseases in which abnormal accumulation of misfolded proteins is toxic to cells.

The study also uncovered what could be a tantalizing clue for understanding cognitive decline in normal aging. When comparing the symptomatic neurons with presymptomatic neurons and with healthy neurons from both young and older adults, the researchers found that the neurons from healthy older adults produced slightly elevated levels of the harmful microRNA, but at far lower levels than the symptomatic neurons from 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 disrupt the healthy cellular balance of autophagy.

"By modeling different stages of the disease across the lifespan, we can see how aging plays a role in the onset of the disease," Yoo said. "With this information, we can begin to look for ways to delay this onset. Our study also suggests that the triggering molecule for the onset of Huntington's disease may play some role in the age-related decline in neuronal function in general. Understanding the component of aging that triggers neurodegeneration may help develop new strategies to treat and prevent Huntington's disease and others neurodegenerative diseases that develop in old age can help.”

Yoo and his team are also collaborating with other collaborators and using their cellular reprogramming technique to study forms of Alzheimer's disease, tauopathy and other neurodegenerative diseases.

Source:

Washington University School of Medicine

Reference:

Oh, YM, et al. (2022) Age-related progression of HD modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy. Nature neuroscience. doi.org/10.1038/s41593-022-01185-4.

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