Aging nerve cells fail to eliminate the intracellular "trash"

Researchers at the Perelman School of Medicine at the University of Pennsylvania have discovered that with age, neurons or nerve cells do not perform an activity as they might when they were younger. The team explains that normal cells eliminate protein and other waste or garbage during an autophagy process. This rids the cell of dysfunctional proteins and unused protein aggregates.

As the cells age, this mechanism fails and, since the nerve cells do not replicate, the proteins tend to accumulate there. This could increase the risk of developing neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis), Alzheimer's disease and Parkinson's disease, the researchers write. The study was published in the last issue of eLife and is entitled "WIPI2B expression neutralizes the age-related decline of autophagosome biogenesis in neurons".

Aberrantly formed autophagosomes accumulate in the neuron of an elderly mouse (Credit: Andrea Stavoe, Penn Medicine, eLife)

The team used live cell imaging or "double labeling of autophagosome biogenesis" of neurons taken from young and elderly mice. Lead authors, Erika Holzbaur, PhD, professor of physiology, and Andrea Stavoe, PhD, postdoctoral fellow in Holzbaur's lab, explain that the autophagy process for cleaning cells from protein debris was a 2016 discovery that was awarded to its discoverers Nobel Prize in Physiology or Medicine in 2016. The co-investigators of the study were Pallavi Gopal of Yale University and Andrea Gubas and Sharon Tooze of the Francis Crick Institute of London .

The team wrote, "Young neurons appear to be very effective at eliminating dysfunctional organelles and protein aggregates, but few studies have examined autophagy in older neurons. Given that age is the single most important risk factor in neurodegenerative diseases, it is essential to understand how changes in autophagy with neurons with age are crucial to understanding the neurodegenerative diseases. "Mr. Holzbaur said, "The decline in autophagy makes neurons more vulnerable to environmental risks. What motivates our line of research is that most neurodegenerative diseases in which a deterioration of autophagy is involved, such as ALS and Alzheimer's, Huntington's and Parkinson's diseases , are also aging disorders. "

The researchers wrote that the process of autophagy (self-self; phagy-eating) begins with the development of an autophagosome in the cell. This autophagosome feeds on damaged structural proteins, misfolded proteins that would not be used by the cell, and structures to be demolished and degraded. These protein wastes are then sequestered in the "biological waste bag" until the autophagosome fuses with the lysomome in the cell. The lysosome contains powerful enzymes that can break down proteins and other wastes and recycle materials that can be reused. Thus, the cell is cleared of debris. The team wrote: "The biogenesis of autophagosomes, conserved from yeast to humans, involves more than 30 proteins that act in separate protein complexes to engulf a bulk cytoplasm or a specific cargo in a double membrane."

In case of failure of this process, there would be a build-up of waste in the cells, which could eventually kill neurons or nerve cells, the researchers explained. Stavoe said, "Think of the streets of the city during a sanitation worker strike."

In their study, the team evaluated mouse neurons during the aging process. They noted that with age, the production of autophagosomes decreased significantly. The autophagosomes produced in older neurons also had significant defects, they noted. These small and poorly formed autophagosomes led to the accumulation of protein debris in mouse neurons. Stavoe added that the brains of donors have shown that people with neurodegenerative disorders have the same number of fewer identical forms of autophagosomes.

The researchers noted that one of the proteins called WIPI2B in older mice, when it was activated, could help older mice produce a sufficient number of autophagosomes. This means that the whole process of eliminating protein waste is coming back in time, the researchers wrote. The team focused on activating this protein and added that it could help regulate biologically the formation of autophagosomes. Stavoe said, "This amazing and comprehensive rescue of autophagy with the help of a protein suggests a new therapeutic target for age-badociated neurodegeneration. autophagosomes.

The authors concluded: "Ultimately, we have shown that the autophagosome biogenesis rate decreased in neurons during aging, but we mitigated this decrease by overexpressing a single component of autophagy, WIPI2B."

The study was funded by the NIH Pathways to Independence Fellowship and by a Javits Award from NINDS.