A little mess never killed anyone, right? Wrong. Researchers 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. "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 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 the lead.
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. "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.
http://www.tmd.ac.jp/english/press-release/20201021-1/index.html
https://www.nature.com/articles/s41467-020-18892-w
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fwipi3-is-essential-for&filter=22
Role of alternative autophagy in neurodegeneration
- 999 views
- Added
Edited
Latest News
Manipulating mitochondrial…
By newseditor
Posted 07 Dec
Guiding cells to natural ta…
By newseditor
Posted 07 Dec
Mechanism of nucleolar vacu…
By newseditor
Posted 06 Dec
Traumatic memories can rewi…
By newseditor
Posted 06 Dec
The tongue might also detec…
By newseditor
Posted 06 Dec
Other Top Stories
Breaking down processed foods by human gut microbes
Read more
RNA splicing errors mediated by tau linked to Alzheimer's disease
Read more
Compromised nuclear maintenance implicated in aging!
Read more
A protein controlling benzodiazepine action identified!
Read more
Linking synaptic activity to sleep!
Read more
Protocols
Brain-wide circuit-specific…
By newseditor
Posted 05 Dec
Cheap, cost-effective, and…
By newseditor
Posted 03 Dec
Temporally multiplexed imag…
By newseditor
Posted 02 Dec
Efficient elimination of ME…
By newseditor
Posted 01 Dec
Personalized drug screening…
By newseditor
Posted 30 Nov
Publications
rRNA intermediates coordina…
By newseditor
Posted 06 Dec
Epigenomic dissection of Al…
By newseditor
Posted 06 Dec
Activity-dependent organiza…
By newseditor
Posted 06 Dec
Innate immunity: the bacter…
By newseditor
Posted 06 Dec
The proton channel OTOP1 is…
By newseditor
Posted 06 Dec
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar