IIT Mandi team shows possible role of signal peptide aggregation in Alzheimer’s disease

NEW DELHI: The Indian Institute of Technology, Mandi’s researchers led by Dr Rajanish Giri, Associate Professor, School of Basic Sciences, IIT Mandi, have discovered an important biomolecular mechanism for the formation of protein clusters or aggregates that are often seen in Alzheimer’s disease.

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“They have shown that the signal peptide of the Amyloid Precursor Protein (APP) can co-aggregate with Amyloid beta peptide (Aβ42). This Aβ42 is known for the pathogenesis of Alzheimer’s disease, a most common form of dementia that slowly destroys memory and other important mental functions,” an IIT Mandi statement said.

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

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Speaking about his recent work, Giri said: “...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.”

Signal peptides are small 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. Usually, as the protein reaches its destination, the signal peptides are cut off from the proteins and often degraded by the cellular machinery. It is possible that they could combine with other peptides to form mis-folded aggregates like Aβ42 that deposit outside of cells and cause diseases.

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The inter-institutional team comprising researchers from IIT Mandi, University of Cambridge, UK, and University of South Florida, USA, studied the aggregation pattern of a signal peptide of the APP. They found that the signal peptide of APP protein after being cut-off associates with Alzheimer's disease-associated peptide Aβ42 and forms aggregates with higher toxicity.

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