Tagging the Trash: Turnover of Toxic Huntingtin 

When it comes to clearing up the mess created by mutant Huntingtin (HTT) we tend to think of sending external help into the brain, in the form of HTT lowering drugs or anti-sense oligonucleotides (ASOs). It’s easy to forget that our bodies have their own clean up crew and trash disposal systems which are responsible for removing toxic and aggregated proteins. 

In a recent study, teams led by Dr. Aaron Ciechanover at the Technion Israel Institute of Technology and Dr. Huu Phuc Nguyen at Ruhr University Bochum in Germany showed that blocking two specific sites on the HTT protein stops it from being labeled as junk, and prevents the brain’s natural trash disposal system from clearing it away. This study suggests that we can promote better clearance of toxic HTT by adding more “junk labels” to it, so the brain knows to take out the trash! 

The body’s built-in recycling and trash disposal system

Cells in our body have a trash-disposal system to remove any damaged or misfolded proteins before they become a problem. These proteins are labelled with a tag called ‘ubiquitin,’ (pronounced ‘yoo-BIK-wih-tin’) that marks them for disposal.

Imagine the cells in our body are like busy warehouses. Tagging proteins with ubiquitin is like putting bright orange sticky notes on junk or broken packages so that the clean-up crew knows to throw them away. Without those sticky notes the junk packages just build up on the warehouse floor, getting in the way and hindering efficient function in the warehouse.

Similarly, interfering with the ubiquitin tagging system can cause the accumulation of junk proteins in cells, and eventually the formation of clumps known as protein aggregates, which can have toxic effects on cells. 

Proteins are made up of long chains of amino acid building blocks, and only specific amino acids in the sequence can be tagged with ubiquitin. Imagine that each package only has certain tagging spots where the disposal sticky notes can be placed. 

In this study the authors looked at the effects of altering two of these tagging sites in the toxic HTT protein, amino acids 6 and 9, so that they can no longer be tagged with ubiquitin and marked for disposal. Now there’s nowhere for those bright orange sticky notes to go.

Improper trash disposal = bigger piles of junk

The scientists created two HD mouse models: one with the normal ubiquitin tagging system still in place (Q134^KK) and one where amino acids 6 and 9 have been changed so they can no longer be tagged for disposal (Q134^RR).

They compared the mice to see how the garbage strike affected properties of the toxic HTT protein. Without ubiquitin tagging, the Q134^RR mice had higher levels of toxic, mutant HTT. Additionally, their mutant HTT aggregates were larger in size. Without adequate labels to mark the protein as junk, it starts to pile up and become an obstruction to the cell.  

More junk = quicker disease progression

The Q134^RR mice which could not label mutant HTT as junk have a greater reduction in the weight of their brains compared to Q134^KK mice. This means there is more degeneration and loss of brain tissue. There was also a lot more inflammation in these mice than in the Q134^KK mice. 

The researchers also ran tests to look at the motor function of the mice, such as measuring how long they can stay on a rotating rod, measuring how they walk, and recording tremors and movements in their sleep. The Q134^RR mice developed movement problems earlier, and their symptoms progressed quicker than the Q134^KK mice. 

Finally, the researchers also looked at how levels of genes were changed when mutant HTT was not labeled as trash. This means they studied how networks of genes are abnormally turned on or turned off compared to control mice.

In the Q134^RR mice, more genes were affected, leading to a more severe form of disease, closer to what is seen in people with HD. This data again emphasizes that blocking the action of the body’s clean-up crew is detrimental in HD.

What does this mean for HD?

This study highlights the importance of the body’s own clean-up crew in helping to prevent excessive build up of mutant HTT. When mutant HTT can no longer be tagged for disposal, the disease gets dramatically worse.

This suggests that finding a way to encourage our clean-up crews to work overtime may be beneficial. Interestingly, an FDA approved drug called desonide has previously been shown to promote ubiquitin tagging of HTT and suppress mutant HTT toxicity. The next step would be to try adding more garbage tags to mutant HTT, to see if that could slow the effects of HD.

Summary:

• The body has its own clean up crew for dysfunctional or unwanted proteins.
• Mutant HTT is prone to forming clumps (aggregates), requiring cleanup to prevent dysfunction in the cell.
• Labels (ubiquitin) can be added to mark mutant HTT for disposal.
• Removing the space where these labels are added led to the accumulation of mutant HTT, which made symptoms worse in HD mice. 
• Tagging mutant HTT with ubiquitin is extremely important in helping clear the toxic protein, and if we can stimulate the body’s natural clean up crew even more it may be beneficial for HD.