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Scientists create a molecular tool to remove toxic proteins from neuronal models of dementia

Alzheimer's disease

PET scan of a human brain with Alzheimer's disease. Credit: public domain

Taking advantage of a probe used for brain imaging in the diagnosis of Alzheimer's disease and related dementias, scientists from the Dana-Farber Cancer Institute and Massachusetts General Hospital (MGH) successfully eliminated patient-derived brain cells of an abnormal protein associated with dementia and other neurogenerative disorders.

The results, reported in the journal eLife, provide a new tool to study the accumulation of abnormal tau protein that occurs in brain cells of patients with Alzheimer's and other forms of dementia, the researchers say. It can help to examine the effects of rapid removal of abnormal tau from cells and may also suggest ways to prevent or reverse a protein buildup.

"Tau plays an important role in the cell: it binds and stabilizes structures called microtubules, which give cells their shape," says Fleur Ferguson, Ph.D., of Dana-Farber, co-author of the study with M. Catarina Silva , Ph.D., of MGH. "However, in neurodegenerative diseases such as Alzheimer's, frontotemporal dementia [FTD]and progressive supranuclear palsy, abnormal accumulations of tau in brain cells, which may be linked to disease progression. We want to understand more about the role these aberrant proteins play in the disease ".

The new tool was created by taking a molecular probe used in positron emission tomography (PET) for Alzheimer's or other tau-related diseases and modifying ¬it for a new purpose. The probe, called T807, binds specifically to the abnormal tau protein. When the probe is labeled with a radioactive isotope, its binding to abnormal tau can be detected by a PET scanner, indicating the presence of a disease.

To equip the T807 with its new use, the researchers left the radioactive label and instead linked the compound to a molecule called the E3-ligase recruitment ligand, which binds to the cell's mechanisms to destroy unwanted proteins . The new double-action form of T807, called QC-01-175, grabs both the abnormal tau and the protein degradation mechanism, bringing them closer together. This proximity allows the abnormal tau to be ubiquitinated bound to ubiquitin proteins, a modification that is essentially defined as cellular garbage. The ubiquitination sends the unwanted tau to the cell proteasome, where it is decomposed and eliminated. Indeed, QC-01-175 becomes a device for feeding toxic tau into the cell's waste disposal system.

When the researchers tested the new tool for tau degradation in laboratory cultures of neurons derived from patients with tau mutations linked to FTD and cells from healthy volunteers, it worked as expected. It eliminated the abnormal tau from the cells of patients with FTD despite having minimal effect on tau in neurons from healthy volunteers. (It showed some off-target effects, interfering with a small number of proteins other than the abnormal tau, but the researchers have strategies to reduce these effects.) Importantly, treatment of FTD cells with QC-01-175 reduced the vulnerability. to stress and improved their survival, indicating that abnormal tau degradation may have therapeutic benefits.

The results demonstrate the value of QC-01-175 as a research tool, the authors of the paper say, useful for exploring the process of abnormal accumulation of tau and the effects on cells of rapid protein removal. They also highlight how protein degradation technology can be used to transform a protein ligand into a functional molecule with pharmacological effects on cells. Researchers are now exploring this strategy in animal models of dementia and expanding the work to identify additional proteins that drive neurodegeneration.

"This innovative protein proximity control strategy to enable targeted protein degradation is a powerful approach to potentially developing therapies for what were otherwise intractable brain diseases," says Stephen J. Haggarty, Ph.D., of MGH Department of Neurology, the co-senior author of the article with Nathanael Gray, Ph.D., of Dana-Farber. "We are extremely excited about the potential for further translation of these tools to enable the development of new therapies for a wide range of neurological diseases."

An unexpected path for the treatment of neurodegenerative diseases

More information:
M Catarina Silva et al, Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models, eLife (2019). DOI: 10.7554 / eLife.45457

Diary information:

Supplied by
Massachusetts General Hospital

Scientists create a molecular tool to remove toxic proteins from neuronal models of dementia (2019, April 9)
recovered on 10 April 2019
from https://medicalxpress.com/news/2019-04-scientists-molecular-tool-toxic-protein.html

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