A research team from the Indian Institute of Technology Mandi led by Dr Rajanish Giri, Associate Professor has discovered an important biomolecular mechanism for the formation of protein clusters/aggregates that are often seen in Alzheimer’s disease.

The findings of the research team have been recently published in the journal ‘Cell Reports Physical Science’ and it will help in future research that could provide the relation of other signal peptides to disease pathogenesis.

The paper has been co-authored by Dr. Rajanish Giri along with research scholars Dr. Kundlik Gadhave and Taniya Bhardwaj and Prof Michele Vendruscolo from the University of Cambridge and Prof Vladimir Uversky from the University of South Florida, US.

The study has shown that signal peptide of the Amyloid Precursor Protein (APP) can co-aggregate with Amyloid beta-peptide (Aβ42) which is known for the pathogenesis of Alzheimer’s disease, a form of dementia that slowly destroys memory and other important mental functions.

While proteins are essential for virtually every process within the cell, their disturbed functions due to aggregation or misfolding can result in harmful effects. There are more than 50 diseases that are associated with protein aggregation/misfolding.

Alzheimer’s disease, for example, is linked with the deposition of misfolded peptides called Amyloid β42 (Aβ42) in the spaces between nerve cells. Aβ42 is a peptide derived from full-length protein Amyloid Precursor Protein (APP).

Generally, when proteins get aggregated or misfolded, they deposit around the cells and kill them, leading to the onset of many diseases.

Speaking about his recent work, Dr Rajanish Giri said, “In Amyloid precursor protein, so far only the Aβ region was known to form toxic aggregates.

Here, we discovered that Signal peptide of Amyloid precursor protein not only forms cell-killing aggregates but also enhances the aggregation of Aβ42 peptide, under in-vitro conditions.”

He stated that signal peptides are short peptide units present at the N-terminus of the proteins, which play a role in protein targeting.

They act as a postal address for the proteins inside the cell and usually, as the protein reaches its destination, the signal peptides are cut off from the proteins and often degraded by the cellular machinery.

“Can they affect other cellular processes? It is possible that they could combine with other peptides to form misfolded aggregates like Aβ42 that deposit outside of cells and cause diseases.

This is the first report on an aggregation of signal peptides in isolation and our study shows a possible link between signal peptide aggregation and Alzheimer’s Aβ42 peptide aggregation,” he added.

This study will help in future research that could provide the relation of other signal peptides to disease pathogenesis, feels Dr Giri on the future implications of this work.