Protein folding factors play a key role in neurodegeneration


For the first time, researchers have mapped out the proteins implicated in the early stages of motor neurone disease (MND).

They have developed a longitudinal map of the proteins involved in MND across the trajectory of the disease, identifying potential therapeutic pathways for further investigation.

“The map is a springboard for many more projects exploring the proteins activated and repressed during the onset, early and late stages of MND,” the senior author said.

“These proteins are biological factors that drive disease onset and progress its development over time.

“We measured differences in protein levels in the brain across the trajectory of the disease and collated this information into a longitudinal map.”

The map is now available for scientists worldwide and will accelerate investigations into MND.

The authors have been working in mouse models of MND to understand the mechanisms driving TDP-43 pathology in the brain, which accounts for 95% of amyotrophic lateral sclerosis (ALS) cases and 50% of frontotemporal lobar degeneration (FTLD). 

Building on the mapping project, the authors chose to focus on a protein-folding factor called DNAJB5.

“Before the onset of MND in mouse models, we observed a marked increase in protein groups responsible for physically assisting in the protein folding process. 

“One of these ‘chaperone’ proteins, DNAJB5, was particularly abundant early on, sparking our curiosity about its role in disease progression.

“In human brain tissue, we found DNAJB5 enriched in areas where TDP-43 aggregates.

“The short-term elevation of DNAJB5 is likely a protective mechanism by neurons in an attempt to control TDP-43 as it begins to dysfunction.

DNAJB5 over-expression decreased TDP-43 aggregation in cell and cortical neuron cultures, and knockout of Dnajb5 exacerbated motor impairments caused by AAV-mediated cytoplasmic TDP-43 expression in mice. 

“This protective response to TDP-43 needs further investigation because it may help us identify preventative and therapeutic approaches to MND.”

This paper was published in Nature Communications.

https://www.nature.com/articles/s41467-024-45646-9

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fa-transient-protein&filter=22

Edited

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