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Taking out the trash is essential for brain health

Date:
November 19, 2020
Source:
Tokyo Medical and Dental University
Summary:
Researchers have identified a protein called Wipi3 that is essential for cellular waste disposal via the alternative autophagy system. Deletion of Wipi3 in the brains of mice causes growth and motor defects attributed to neuronal accumulation of iron, resulting in neurodegeneration. However, over-expression of another alternative autophagy protein, Dram1, reverses the effects in Wipi3 deficiency, and may represent a novel treatment for neurodegenerative diseases.
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A little mess never killed anyone, right? Wrong. Researchers at Tokyo Medical and Dental University (TMDU) have recently shown that a build-up of cellular "trash" in the brain can actually cause neurodegeneration, and even death.

Reporting their findings in Nature Communications, the researchers describe how defects in a cellular waste disposal mechanism, called "alternative autophagy," can lead to a lethal build-up of iron and protein in brain cells.

"Cells are constantly clearing out dysfunctional or unnecessary components, which are then degraded and recycled," explains study lead author Hirofumi Yamaguchi. "Autophagy is the process whereby unwanted cellular components and proteins are contained within a spherical doubled-membraned vesicle called an autophagosome, which fuses with an enzyme-filled lysosome to form an autolysosome. The waste material is then broken down and reused by the cell."

This common form of autophagy, called "canonical autophagy," is well characterized and involves a suite of autophagy-related proteins, such as Atg5 and Atg7. More recently though, several Atg5-independent alternative autophagy pathways have also been described, the biological roles of which remain unclear.

After identifying alternative autophagy-related proteins in yeast, the team at TMDU focused on a mammalian ortholog called "Wipi3," which had previously been implicated in canonical autophagy. "When we deleted Wipi3 in a mouse cell line and induced alternative autophagy, we no longer observed the formation of double-membraned autophagosomes or single-membraned autolysosomes, confirming that Wipi3 is essential for alternative autophagy," says Yamaguchi.

Mice containing a brain-specific deletion of Wipi3 demonstrated growth and motor defects most commonly seen in patients with neurodegeneration, with the researchers also noting an accumulation of iron and the iron-metabolizing protein ceruloplasmin in the brain cells of affected mice.

"Iron deposition has been flagged as a possible trigger in various neurodegenerative disorders, and is usually associated with the abnormal accumulation of iron-binding proteins," explains study senior author Shigeomi Shimizu. "Our findings are strong evidence that alternative autophagy, and Wipi3 specifically, may be essential for preventing this toxic build-up of iron."

Interestingly, although Wipi3-deficient and Atg7 (canonical autophagy)-deficient mice showed similar motor defects, they exhibited very different sub-cellular changes, suggesting that alternative autophagy and canonical autophagy act independently to protect neurons. Supporting this, deletion of both Wipi3 and Atg7 in mice was almost always fatal.

The researchers are hopeful that this research could lead to the development of neuroprotective drugs. Preliminary tests indicate that over-expression of Dram1, another alternative autophagy-associated protein, can reverse the effects of Wipi3 deletion, and may form the basis of future therapies for various neurodegenerative diseases.


Story Source:

Materials provided by Tokyo Medical and Dental University. Note: Content may be edited for style and length.


Journal Reference:

  1. Hirofumi Yamaguchi, Shinya Honda, Satoru Torii, Kimiko Shimizu, Kaoru Katoh, Koichi Miyake, Noriko Miyake, Nobuhiro Fujikake, Hajime Tajima Sakurai, Satoko Arakawa, Shigeomi Shimizu. Wipi3 is essential for alternative autophagy and its loss causes neurodegeneration. Nature Communications, 2020; 11 (1) DOI: 10.1038/s41467-020-18892-w

Cite This Page:

Tokyo Medical and Dental University. "Taking out the trash is essential for brain health." ScienceDaily. ScienceDaily, 19 November 2020. <www.sciencedaily.com/releases/2020/11/201119103055.htm>.
Tokyo Medical and Dental University. (2020, November 19). Taking out the trash is essential for brain health. ScienceDaily. Retrieved July 18, 2024 from www.sciencedaily.com/releases/2020/11/201119103055.htm
Tokyo Medical and Dental University. "Taking out the trash is essential for brain health." ScienceDaily. www.sciencedaily.com/releases/2020/11/201119103055.htm (accessed July 18, 2024).

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