The brain requires order

A group of researchers from the Tokyo Medical and Dental University (TMDU) has discovered that the Wipi3 protein involved in the disposal of cellular waste is of great importance for the health of neurons. They showed that defects in the mechanism of cellular waste disposal can lead to a fatal accumulation of iron in brain cells.

Cells constantly remove damaged or unnecessary components, which are then decomposed and recycled. Autophagy is a process in which unnecessary cellular components and proteins are placed in a vesicle with a double membrane (autophagosome), which merges with a lysosome filled with enzymes to form an autolysosome. The waste is then disposed of and reused in the cage.

The autophagy system works thanks to the proteins Atg5 and Atg7 – this is the so-called classical autophagy. However, more recently, several alternative Atg5-independent autophagy mechanisms have been described, the biological role of which remains unclear.

After identifying alternative proteins in yeast, the research team focused on its mammalian counterpart, the Wipi3 protein. When the researchers turned off the expression of Wipi3 in mouse cell lines and induced alternative autophagy, the formation of autolysosomes stopped, which proves the important role of Wipi3 for alternative autophagy.

Mice with Wipi3 deletion in brain cells showed motor disorders most often observed in patients with neurodegenerative diseases, while the researchers also noted the accumulation of iron and iron-metabolizing protein ceruloplasmin in the brain cells of experimental mice.

Iron accumulation is considered a possible trigger of various neurodegenerative disorders and is usually associated with an abnormal accumulation of iron-binding proteins. The Wipi3 protein, as confirmed by the study, can prevent this toxic accumulation of iron.

Surprisingly, mice with Wipi3 deficiency and mice with Atg7 deficiency showed similar motor disorders, but different cellular changes, which means that both autophagy mechanisms (classical and alternative) independently protect neurons. Disabling both Wipi3 and Atg7 in mice was almost always fatal.

Impaired motor activity of mice with the absence of Wipi3 at the age of 10 weeks. (a) the grasping reflex is observed in control mice.
(b) trace analysis showed motor deficits in mice without Wipi3.

Accumulation of iron and ceruloplasmin in mice without Wipi3. Cryosections of the cerebellum of mice were stained with Berlin blue (a) and immunocolored with antibodies against ceruloplasmin (green) and against calbindin (red) (b). Blue spots indicate iron deposits.

The researchers hope that this work may lead to the development of neuroprotective drugs. Preliminary tests show that overexpression of Dram1, another protein associated with alternative autophagy, can reverse the effects of Wipi3 deletion and form the basis of future treatments for various neurodegenerative diseases.

Article by H.Yamaguchi et al. Wipi3 is essential for alternative autophagy and its loss causes neurodegeneration published in the journal Nature Communications.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru According to TMDU: Taking Out the Trash is Essential for Brain Health.