David Kang, PhD, professor of molecular medicine at the University of South Florida Health’s Byrd Alzheimer Center (USF Health) led the research team that early discovered a defect in the dynamic process of cell waste elimination known as autophagy. Photo credit: © USF Health

In a healthy brain, the multi-step waste disposal process known as autophagy routinely removes and breaks down damaged cellular components – including malformed proteins like tau and toxic mitochondria. These cell debris would otherwise accumulate like uncollected garbage to drive the death of brain cells (neurons) and ultimately destroy cognitive abilities such as thinking, remembering and thinking in patients with Alzheimer’s and certain other neurodegenerative diseases.

The protein p62, a selective autophagy cargo receptor, plays an important role in clearing misfolded tau proteins and dysfunctional mitochondria, the powerhouse in all cells, including neurons. Through autophagy (which means “self-eating” in Greek), old or broken cell material is ultimately digested and recycled in lysosomes, membrane-bound structures that function like mini-waste disposal systems.

Now neuroscientists at the Byrd Alzheimer Center of the University of South Florida Health (USF Health) are reporting for the first time that the protein phosphatase Slingshot-1, SSH1 for short, interferes with the ability of p62 to function as an efficient “garbage collector” and thereby interferes with disposal of both damaged tau and mitochondrial leakage toxins. In a preclinical study, the researchers showed that the influence of SSH1 on stopping the p62-mediated protective clearance of tau from the role of SSH1 in activating cofilin, an enzyme that plays an essential role in worsening tau pathology, was separated.

Their results were published in Autophagy on October 12th.

“Slingshot-1 plays an important role in regulating dew and neurotoxic mitochondrial levels, so understanding exactly what goes wrong when they build up in the brain is important,” said the newspaper’s senior writer David Kang. Ph.D., Professor of Molecular Medicine at USF Health Morsani College of Medicine, who holds the Fleming Endowed Chair in Alzheimer’s Disease and is Director of Basic Research at the Byrd Alzheimer Center. “This study provides more insight into a defect in the p62 signaling pathway that will help us develop SSH1 inhibitors (drugs) to stop or slow down Alzheimer’s disease and related neurodegenerative diseases.”

At the beginning of their study, Dr. Kang, including first author and PhD student Cenxiao (Catherine) Fang, suggested that the TBK1 enzyme temporarily adds phosphate to eliminate bad mitochondria (known as mitophagia) p62. Phosphate is added specifically at the site of amino acid 403 (SER403), which activates p62. Until now, however, no scientist had found out which enzyme removes phosphate from p62, known as dephosphorylation.

Tightly controlled phosphorylation is required to equilibrate p62 activation. This is an important step in improving the ability of the cargo receptor to recognize and collect cell debris marked as “garbage” by a ubiquitin tag. Simply put, when autophagy is working well, ubiquitinated dew and ubiquitinated mitochondria are purposefully collected and then delivered for destruction and recycling by autophagosomes (the garbage trucks in this dynamic process). However, the garbage collector p62 does not affect the healthy (unlabeled) proteins and organelles of the cell.

In a series of gene deactivation and overexpression experiments using human cell lines, primary neurons, and a mouse model of tauopathy, Dr. Kang’s team SSH1, which acts specifically on SER403, as the first enzyme to remove this key phosphate from p62 and cause p62 to be deactivated.

“When something gets out of whack, such as the overactivation of Slingshot-1 by Alzheimer’s-related protein Aβ, SSH1 begins to remove the phosphate from the p62 garbage collector and essentially transmits the message ‘stop, don’t continue your job’ “This leads to dire consequences like the accumulation of damaged tau proteins and toxic mitochondria,” said Dr. Kang.

“If we can rebalance phosphorylation regulation by inhibitors that dampen overactive Slingshot-1, we can increase the normal activity of p62 in removing the toxic waste.”

This latest study builds on previous USF Health research showing that Aβ-activated cofilin, which occurs through SSH1, essentially passes tau out of microtubules and provides structural support to neurons, thereby promoting the formation of tau tangles in dying nerve cells . During the displacement process, cofilin is transported into the mitochondria and the energy-producing mitochondria are damaged. After this collateral damage caused by cofilin, Dr. Kang’s team used widespread mitophagy to remove the diseased mitochondria.

“We got exactly the opposite result, which meant there was another mechanism that was affecting the regulation of mitochondria by Slingshot-1,” said Dr. Kang, “and it turned out to include the main autophagy machines of p62.”

The researchers also showed that two important and completely separate signaling pathways involved in tau pathology – one for p62 and one for cofilin – are regulated by the same enzyme, SSH1.

“In addition to the SSH1-cofilin activation pathway in promoting tau displacement from microtubules, this study demonstrates the divergent SSH1-p62 inhibition pathway in impairing the autophagic clearance of misfolded tau,” the study’s authors report.

Cofilin may be an early culprit in a tauopathy process that leads to brain cell death

More information:
Autophagy (2020). DOI: 10.1080 / 15548627.2020.1816663 Provided by the University of South Florida

Quote: The enzyme SSH1 interferes with the disposal of accumulating cell waste and leads to the death of brain cells (2020, October 12), accessed on October 12, 2020 at https://medicalxpress.com/news/2020-10-enzyme-ssh1- impairs-disposal-accumulating. html

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