Flexible nanopores shed new light on Parkinson's and ALS

In a promising new milestone for nanotechnology, Constructor University has contributed to a study that demonstrates self-assembling nanopores capable of detecting disease proteins associated with illnesses like Parkinson's and ALS. The international research project, published in the prestigious journal Nature Nanotechnology, produced synthetic nanoscale pores that adjust like a camera aperture to capture and analyze different proteins at low concentrations—even distinguishing between healthy proteins and the dangerous mutated versions that contribute to disease.

Constructor University Professor Dr. Ulrich Kleinekathöfer and Post-Doctoral researcher Dr. Kalyanashis Jana contributed computational expertise to the study led by Dr. Kozhinjampara Mahendran at the Rajiv Gandhi Centre for Biotechnology in India. "We supported the experimental work done by our colleagues in India by providing computational simulations that allow us to learn the molecular-level details of these nanopores and their sensing of analytes," said Prof. Kleinekathöfer.

Deciphering the invisible drivers of Parkinson’s and ALS

"Our simulations helped with rationally designing flexible, synthetic pores that can intrinsically detect disordered proteins. We know these molecules contribute to neurodegenerative diseases like Parkinson's, but they are notoriously difficult to study using conventional methods because they constantly change shape," explained Prof. Kleinekathöfer.  

The innovation lies in the nanopores' flexibility. By strategically incorporating a single unnatural amino acid into a designed peptide, the research team effectively created molecular sensors that can adjust between small and large diameters while maintaining their structural foundation. This versatility allows the same basic design to detect different types of disease proteins.

The larger pores excel at capturing and analyzing α-synuclein, a protein whose abnormal clumping is a primary hallmark of Parkinson's disease. The nanopores achieved nanomolar sensitivity, meaning they were able to detect trace amounts of the protein, and could also distinguish between different disease-causing mutations even within heterogeneous mixtures. Smaller pores also successfully detected peptides associated with ALS and cellular death.

Conventional techniques like enzyme-linked immunosorbent assays (ELISA) or mass spectrometry require larger sample volumes, often being unable to detect proteins at such low concentrations, and typically cannot distinguish between different aggregation states in real-time. By contrast, the nanopore approach successfully provided single-molecule resolution with minimal sample requirements.

Perhaps most significantly, the technology allowed researchers to track in real-time how harmless individual protein molecules misfold and cluster into toxic aggregates that damage brain cells. Understanding this aggregation could open the door for future interventions such as drugs that prevent or slow the formation of toxic protein clumps. By watching this process at the single-molecule level, researchers can identify which intermediate states are most toxic and which transitions might be amenable to therapeutic intervention.

Foundational science: the first step

While the ability to monitor how disease-related proteins clump together opens exciting new avenues for research and possible future treatments, Prof. Kleinekathöfer emphasized the importance of managing expectations.

"This breakthrough represents vital basic science," explained Prof. Kleinekathöfer. "While we are thrilled that our computer simulations have helped unlock these mechanisms, many developmental steps will still be needed before this laboratory technology can be translated into diagnostic tools and treatments for Parkinson’s or ALS patients," he explained. "However, it does represent a highly promising and necessary first step."

The high-profile publication marks the latest contribution of Prof. Kleinekathöfer and his Computational Physics and Biophysics research group to the field of nanotechnology. The study is a continuation of the group's earlier breakthrough work developing the first-ever "mirror-image" nanopores, as published in Nature Communications in October 2025.