Removing Cellular Garbage to Treat Neurodegenerative Disease

Improving the ability of cells to clear out garbage is a potential therapy for a wide range of conditions - probably including aging itself, as the failure of garage clearance mechanisms related to the lysosome contributes to degenerative aging. In past years researchers have noted that calorie restriction seems to boost garbage clearance and the cellular recycling known as autophagy, while making autophagy more efficient has been used to rejuvenate liver function in old mice.

Here researchers are tinkering with garbage clearance in the brain as a way to treat neurodegenerative conditions, many of which seem to involve a buildup of unwanted and harmful compunds inside cells:

[Researchers] found that the issue in amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) is the inability of the cell's protein garbage disposal system to "pull out" and destroy TDP-43, a powerful, sometimes mutated gene that produces excess amounts of protein inside the nucleus of a nerve cell, or neuron.

The way to rev up protein disposal is to add parkin - the cell's natural disposal units - to brain cells. In this study, [researchers] demonstrated in two animal experiments that delivering parkin genes to neurons slowed down ALS pathologies linked to TDP-43. [The] study further demonstrates that clumps known as "inclusions" of TDP-43 protein found inside neuron bodies in both disorders do not promote these diseases, as some researchers have argued.

What happens in both diseases is that this protein, which is a potent regulator of thousands of genes, leaves the nucleus and collects inside the gel-like cytoplasm of the neuron. In ALS, also known as Lou Gehrig's disease, this occurs in motor neurons, affecting movement; in FTD, it occurs in the frontal lobe of the brain, leading to dementia.

"Our study suggests TDP-43 in the cell cytoplasm is deposited there in order to eventually be destroyed - without contributing to disease - and that TDP-43 in the nucleus is causing the damage. Because so much protein is being produced, the cell can't keep up with removing these toxic particles in the nucleus and the dumping of them in the cytoplasm. There may be a way to fix this problem."

[Researchers] found that parkin "tags" TDP-43 protein in the nucleus with a molecule that takes it from the nucleus and into the cytoplasm of the cell. "This is good. If TDP-43 is in the cytoplasm, it will prevent further nuclear damage and deregulation of genetic materials that determine protein identity, We think parkin is tagging proteins in the nucleus for destruction, but there just isn't enough parkin around - compared with over-production of TDP-43 - to do the job."



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