Researchers determine protein produced after stroke that triggers neurodegeneration

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Researchers identify protein produced after stroke that triggers neurodegeneration

AIF3 splice triggers neurodegeneration and neuron loss in a mouse brain, as shown in the cortex (orange and pink), hippocampus (green), and thalamus (blue). Photo credit: UT Southwestern Medical Center

Researchers at the Peter O & # 39; Donnell Jr. Brain Institute at UT Southwestern have identified a new protein implicated in cell death and a potential therapeutic target that could prevent or delay the progression of neurodegenerative diseases after stroke.

Scientists from the UTSW's Pathology, Neurology, Biochemistry and Pharmacology departments have identified and named AIF3, an alternative form of apoptosis-inducing factor (AIF), a protein that is essential for the maintenance of normal mitochondrial function. As soon as AIF is released from the mitochondria, it triggers processes that trigger a type of programmed cell death.

In a study published in the journal Molecular Neurodegeneration, the team at UT Southwestern worked with researchers from the medical school at Johns Hopkins University and found that the brain switches from producing AIF to producing AIF3 after a stroke. They also reported that stroke triggers a process known as alternative splicing, in which some of the instructions encoding AIF are removed, resulting in the production of AIF3. Incorrect splicing can lead to disease, but changing the splicing process can offer potential for new therapies.

AIF3 levels were elevated after a stroke in both human brain tissue and mouse models developed by researchers. In mice, the stroke-induced production of AIF3 resulted in severe progressive neurodegeneration, suggesting a possible mechanism for a severe side effect of stroke that has been observed in some patients. Stroke has been recognized as the second leading cause of dementia, and it is estimated that 10 percent of stroke patients will develop post-stroke neurodegeneration within a year.

The molecular mechanism underlying the neurodegeneration induced by AIF3 splicing includes the combined effect that the original form of AIF is lost and, in addition, the modified AIF3 is obtained, which leads to both mitochondrial dysfunction and cell death.

"AIF3 splice causes mitochondrial dysfunction and neurodegeneration," says senior author Yingfei Wang, Ph.D., assistant professor of pathology and neurology and a member of the O & # 39; Donnell Brain Institute. "Our study provides a valuable tool for understanding 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 in understanding the aftermath of a stroke that affects nearly 800,000 US residents annually. According to the Centers for Disease Control and Prevention (CDC), stroke kills one person every four minutes, and about one in six deaths from cardiovascular disease is attributed to stroke – with ischemic strokes accounting for about 87 percent of all cases. The main causes of strokes are high blood pressure, high cholesterol, smoking, obesity and diabetes. Stroke also disproportionately affects certain populations and is more common in men, although more women than men die from stroke. CDC figures show that blacks have twice the risk of a first stroke than whites and a higher risk of death. Hispanic populations have seen death rates rise since 2013, while other populations have not.

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More information:
Shuiqiao Liu et al., AIF3 splice switch, triggers neurodegeneration and molecular neurodegeneration (2021). DOI: 10.1186 / s13024-021-00442-7

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UT Southwestern Medical Center

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