Researchers have shown that hundreds of proteins and mRNA molecules are found in the wrong place in nerve cells affected by Motor Neuron Disease (MND), also known as Amyotrophic Lateral Sclerosis (ALS).
ALS is a rapidly progressing and devastating condition that causes paralysis by affecting motor neurons, with limited treatment options. Until now, scientists were aware that a few proteins, especially a protein called TDP-43, were found in unexpected locations in ALS nerve cells.
But new research published in Neuron shows that the problem is much broader. This ‘mislocalisation’ affects many more proteins than first thought, especially those involved in RNA binding. The mislocalisation extends to mRNAs too, molecules that deliver instructions to make proteins from the DNA in the nucleus.
The researchers used stem cells from patients to create motor neurons with ALS-causing mutations in the TARDBP and VCP genes. They then separated the two main compartments of the cell (nucleus and cytoplasm), and analysed all the mRNA and protein within each. They found that in ALS cells, hundreds of mRNAs and proteins were mislocated compared to healthy cells.
They observed proteins and mRNAs relocating from the cell’s nucleus (the ‘control centre’) into the cytoplasm (the ‘body’ of the cell) or vice versa, hinting at potential transport issues within the cell.
The researchers also saw that mislocated mRNAs and proteins interacted more with each other, compared to those in the right place. They speculate that as the mRNAs and proteins mislocalise, they may drag each other with them, creating a domino effect.
Remarkably, the mislocalisation of proteins and mRNAs was partially improved with a drug called ML240, which blocks the action of the VCP enzyme. Blocking this enzyme also led to other beneficial effects on cell function, such as reducing the level of damage to DNA.
The senior author said: “For the patients I see, it’s devastating that there aren’t yet impactful treatments available for ALS. This research represents a shift in our thinking about what causes ALS – it doesn’t involve abnormal movement of just a few proteins, but the abnormal localisation of hundreds of proteins and mRNAs. This opens new avenues for research and potential therapies.
“As ML240 improved the mislocalisation and other disease features in ALS, we now need to understand if this can be a tractable therapy for ALS more widely. This is just the beginning and there is lots more to do, but our work provides some hope for effective therapies.”
The researchers will next investigate protein and mRNA location in other ALS genetic backgrounds. There is also much more work ahead before VCP inhibitors could be used clinically – ML240 hasn’t yet been tested in animals, and potential chemical changes may be necessary to make sure it enters nerve cells without causing side effects.
https://www.cell.com/neuron/fulltext/S0896-6273(23)00478-6
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fnucleocytoplasmic-mrna&filter=22
mRNA redistribution in ALS motor neurons
- 1,675 views
- Added
Latest News
Protein that helps COVID-19…
By newseditor
Posted 26 Jul
Spinal Muscular Atrophy (SM…
By newseditor
Posted 26 Jul
Link between bowel movement…
By newseditor
Posted 26 Jul
Inhibition of IL-11 signall…
By newseditor
Posted 25 Jul
Brain changes linked to obe…
By newseditor
Posted 25 Jul
Other Top Stories
Intestinal wound healing in Crohn's disease is compromised by foodb…
Read more
Modeling viral infections using patient-specific "digital twins"
Read more
How SARS-CoV-2 variants escape neutralization?
Read more
Robust intracellular virulence networks detected!
Read more
SARS-CoV-2 within-host diversity and transmission
Read more
Protocols
A systems biology approach…
By newseditor
Posted 24 Jul
quantms: a cloud-based pipe…
By newseditor
Posted 22 Jul
Emerging tools and best pra…
By newseditor
Posted 19 Jul
Directly selecting cell-typ…
By newseditor
Posted 17 Jul
PUFFFIN: an ultra-bright, c…
By newseditor
Posted 16 Jul
Publications
Hepatocyte-intrinsic SMN de…
By newseditor
Posted 26 Jul
Aberrant bowel movement fre…
By newseditor
Posted 26 Jul
A pseudoautosomal glycosyla…
By newseditor
Posted 26 Jul
Microglia protect against a…
By newseditor
Posted 26 Jul
Rigor and reproducibility i…
By newseditor
Posted 26 Jul
Presentations
Myelin plasticity in the ve…
By newseditor
Posted 10 Jun
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
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