Prevent protein misfolding, new discoveries by Chinese scholars guide new therapies for cancer and Alzheimer's disease

▎Edited by WuXi AppTec content team Many diseases are related to protein misfolding
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For example, in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, misfolded proteins can lead to the formation of pathological plaques and protein tangles
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In some cancers, the mutated tumor suppressor protein misfolds and loses its tumor suppressor effect
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Recently, a research team from the University of Pennsylvania published a paper in the top academic journal Nature, revealing that a protein called DAXX and its family members play a role in promoting the correct folding of other proteins in the cell.

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"This group of proteins actually constitutes a new type of'protein quality control system' in the cell
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" said Professor Yang Xiaolu, who led the research
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The research team also found for the first time that restoring the normal levels of this group of proteins can prevent misfolding of proteins related to neurodegeneration, and can also help cancer-related mutant proteins to restore their normal conformation and reduce their carcinogenic properties
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These findings provide opportunities for the development of new therapies
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▲Professor Yang Xiaolu, the corresponding author (picture source: University of Pennsylvania official website) DAXX protein, also known as death domain related protein, is rich in two amino acid residues, namely aspartic acid (D) and glutamic acid (E), belonging to A large family called polyD/E proteins
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There are more than 50 known members of this protein family, which are involved in gene transcription and regulation of cell cycle and other cellular processes
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This study found that DAXX and several other polyD/E proteins actually play the role of "partners" in directing protein folding
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They work through the polyD/E region to promote the correct folding of proteins, prevent protein aggregation, release existing aggregation, and open up misfolded proteins
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Experiments have shown that DAXX can prevent the misfolding, tangling and formation of extracellular plaques and intracellular aggregates of proteins related to neurodegenerative diseases, such as β-amyloid and α-synuclein
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In the brains of patients with Alzheimer's disease, plaques formed by β-amyloid can be seen between nerve cells.
Eliminating these plaques is the target of various therapies
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In the brains of patients with Parkinson's disease, aggregates of α-synuclein can be observed in cells
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Therefore, this discovery provides a feasible direction for the treatment of neurodegenerative diseases
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▲DAXX (red) prevents mutant p53 protein (dark green) from accumulating in cells (picture source: reference [2]) Another set of experiments shows that DAXX helps restore the natural conformation and function of p53 protein, showing DAXX Potential role in cancer treatment
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p53 protein is a well-known tumor suppressor, and its mutations are related to a series of cancers such as lung cancer, colon cancer, and pancreatic cancer
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The researchers pointed out that enhancing the function of DAXX may be able to rebuild the tumor suppressor function of p53 to treat patients
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"These findings give us a new understanding of the biochemical activity of this type of protein.
This biochemical activity effectively counteracts the protein misfolding seen in neurodegenerative diseases such as Alzheimer’s disease and cancer, and represents a new development.
Opportunity for therapy
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" Professor Yang concluded
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Reference: [1] Huang, L.
, et al.
(2021) DAXX represents a new type of protein-folding enabler.
Nature.
doi.
org/10.
1038/s41586-021-03824-5.
[2] Restoring “Chaperone ”Protein May Prevent Plaque Build-up in Alzheimer's.
Retrieved Sep.
2, 2021 from https:// build-up-in-alzheimers