Researchers at the Peter O’Donnell Jr. Brain Institute at UT Southwestern have identified a new protein involved in cell death that provides a potential therapeutic target that could prevent or delay the progression of neurodegenerative diseases following stroke cerebral.
Scientists from the departments of pathology, neurology, biochemistry and pharmacology at UTSW have identified and named AIF3, an alternative form of apoptosis-inducing factor (AIF), a protein essential for the maintenance of normal mitochondrial function. Once released from the mitochondria, AIF triggers processes that induce a type of programmed cell death.
In a study published in the journal Molecular neurodegeneration, the UT Southwestern team collaborated with researchers at the Johns Hopkins University School of Medicine and found that following a stroke, the brain shifts from AIF production to AIF3 production. They also reported that running triggers a process known as alternative splicing, in which part of the instructions encoding AIF is removed, resulting in the production of AIF3. Defective splicing can cause disease, but altering the splicing process can offer potential for new therapies.
In the human and mouse brain tissue models developed by the researchers, AIF3 levels were elevated after a stroke. In mice, stroke-induced AIF3 production led to severe progressive neurodegeneration, suggesting a potential mechanism for a severe stroke side effect seen in some patients. Stroke has been recognized as the second most common cause of dementia, and an estimated 10 percent of stroke patients develop post-stroke neurodegeneration within a year.
The molecular mechanism underlying AIF3 splicing-induced neurodegeneration involves the combined effect of losing the original form of AIF in addition to gaining altered AIF3, leading to both mitochondrial dysfunction and cell death.
“AIF3 splicing causes mitochondrial dysfunction and neurodegeneration,” says lead author Yingfei Wang, Ph.D., assistant professor of pathology and neurology and member of the O’Donnell Brain Institute. “Our study provides a valuable tool to understand the role of AIF3 splicing in the brain and a potential therapeutic target to prevent or delay the progression of neurodegenerative diseases.”
The results are important for understanding the after-effects of stroke, which strikes nearly 800,000 US residents each year. A stroke kills a person every four minutes, according to the Centers for Disease Control and Prevention (CDC), and about one in six deaths from cardiovascular disease is attributed to a stroke – ischemic strokes accounting for about 87% of all cases. The main causes of stroke are high blood pressure, high cholesterol, smoking, obesity and diabetes. Stroke also disproportionately affects some populations and occurs more often in men, although more women than men die from stroke. CDC figures show blacks are twice as likely to have a first stroke as whites and a higher risk of death. Hispanic populations have experienced increased death rates since 2013, unlike other populations.
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