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Piecing Together the Puzzle of Neurological Diseases

Researchers from POSTECH have uncovered the structural identity of hetero-oligomers nano-aggregates from biomarkers of Alzheimer’s disease and Parkinson’s disease using atomic force microscopy (AFM), laying the foundations to treat neurodegenerative diseases.

Despite our efforts to eat healthy and stay fit, we often neglect our internal health, taxing our minds and giving no rest to the core commander of our body – the brain. Weighing approximately only three pounds, the brain is remarkably complex in controlling all bodily functions from thought and touch, to hunger and temperature. But with great power, comes great vulnerabilities. For the brain, neurological diseases are particularly notable threats.

Of the many neurodegenerative diseases, we may be most familiar with Alzheimer’s and Parkinson’s disease. While Alzheimer’s disease is infamous for its progressive deterioration of memory and cognitive functions, Parkinson’s is characterised by the resultant hand and arm tremors that debilitate regular movement. Nevertheless, both illnesses involve the distortion and death of brain cells known as neurons. With these similarities in mind, scientists have attempted to uncover the underlying mechanisms of neurodegenerative disease pathogenesis but were obstructed by technological constraints.

Fortunately, with the dawn of atomic force microscopy (AFM), a team of researchers, spearheaded by Professor Joon Won Park and Ph.D. candidate Eun Ji Shin of the Department of Chemistry at POSTECH, has successfully uncovered the structural identity of nano-aggregates obtained from amyloid-beta and alpha-synuclein, which are prominent protein biomarkers for Alzheimer’s and Parkinson’s respectively. AFM involves the use of immobilised antibodies to detect the N- and C-terminus of specific peptides.

Using quadruple mapping with four AFM tips, the researchers were able to confirm that these aggregates are hetero-oligomers. Different from homo-oligomers, which are protein aggregates derived from a single peptide (amyloid-beta or alpha-synuclein), hetero-oligomers are derived from multiple peptides. Their findings also showed that peptide ends have a greater propensity to be found on hetero-oligomers than homo-oligomers, hence making these aggregations more loosely packed and easily detected, especially with AFM.

As the first study ever to examine disrupted nano-aggregates of proteins, their novel method and findings are expected to drive forward research in hetero-oligomer aggregation and pave the way to better understand overlapping links with other neurodegenerative diseases.

“Until now, there was no adequate method to analyse the nano-aggregates, making it impossible to elucidate the structural identity of heterogeneous aggregates,” Professor Joon Won Park elaborated. “As the analysis method developed in this study is applicable to other amyloid protein aggregates, it will help to identify the cause of diseases such as Alzheimer’s or the mad cow disease.” [APBN]

Source: Shin, E. J., & Park, J. W. (2021). Nanoaggregates Derived from Amyloid-beta and Alpha-synuclein Characterized by Sequential Quadruple Force Mapping. Nano Letters, 21(9), 3789-3797.