A host of special molecules called nuclear RNA-binding proteins (RBPs), when misplaced outside the nucleus, form the harmful clumps seen in several brain disorders, including frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). "Clumps that form from these disease proteins are composed of sticky fibrils that damage nerve cells," said the senior author. "We want to reverse the formation of these clumps and put the RNA-binding proteins back in their proper place, inside the nucleus."
Normally, nuclear-import receptors (NIRs) bind to specific sequences of amino acids on the RBPs, to shepherd them into the nucleus. The team describes in Cell what happened when they added NIRs to aggregates made from and FUS proteins, which are connected to these neurodegenerative diseases.
"When we increased the concentration of NIRs, there were three important and surprising outcomes," said co-first author. First, clumps of RBPs dissolved in test-tube experiments. Next, NIRs also dissolved cytoplasmic clumps in cells and functional RBPs were returned to the nucleus. And finally, when the expression of NIRs was increased in fruitfly models of disease, lifespan was extended and degeneration was reduced.
"All of this biochemistry was highly unanticipated," said co-first author. "We didn't suspect that the NIRs would break up the clumps, return the RBPs to the nucleus, and mitigate neurodegeneration."
The team was surprised by how rapidly the NIRs could reverse the formation of the FUS and TDP-43 clumps. The transition from the RBP being dissolved in solution to forming droplet-like structures normally happens in the nucleus as a regular part of RBP function. However, when RBPs, like FUS and TDP-43, are misplaced in the cytoplasm, these phase changes can become aberrant, setting the RBPs on a destructive path, which can be corrected with NIRs. But, NIR expression or activity likely becomes reduced in disease.
'Given this complexity, we are now working to find a way to increase expression or activity of NIRs in neurons with clumps using protein engineering or small-molecule drugs, said coauthor.
https://www.pennmedicine.org/news/news-releases/2018/april/putting-proteins-in-their-proper-place
http://www.cell.com/cell/fulltext/S0092-8674(18)30282-4
Latest News
Abusive drugs hijack natura…
By newseditor
Posted 23 Apr
Mechanism of action of the…
By newseditor
Posted 23 Apr
Role of fat in rare neurolo…
By newseditor
Posted 23 Apr
How protein synthesis in de…
By newseditor
Posted 22 Apr
Atlas of mRNA variants in d…
By newseditor
Posted 22 Apr
Other Top Stories
Cholesterol reduction in monkeys by gene editing!
Read more
Addictive behavior gene identified!
Read more
Why baby's sex may influence risk of pregnancy-related complicatations
Read more
Is sleep an antioxidant?
Read more
Memory identity is stored in specific synapses
Read more
Protocols
A programmable targeted pro…
By newseditor
Posted 23 Apr
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Publications
Exploiting pancreatic cance…
By newseditor
Posted 23 Apr
Structure of antiviral drug…
By newseditor
Posted 23 Apr
Type-I-interferon-responsiv…
By newseditor
Posted 23 Apr
Selenium, diabetes, and the…
By newseditor
Posted 23 Apr
Long-term neuropsychologica…
By newseditor
Posted 23 Apr
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