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March 5th, 2025
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Yusuf Hamied Department of Chemistry, UK Dementia Research Institute, University of Cambridge, Cambridge, UK; Molecular Horizons and School of Science, Universi
molecular biology
biorxiv

Fingerprinting disease-derived protein aggregates reveals unique signature of Motor Neuron Disease

Cox, D.Open in Google Scholar•Burke, M.Open in Google Scholar•Milani, S.Open in Google Scholar•White, M. A.Open in Google Scholar•Waldron, F. M.Open in Google Scholar•Böken, D.Open in Google Scholar•Lobanova, E.Open in Google Scholar•Sreedharan, J.Open in Google Scholar•Gregory, J. M.Open in Google Scholar•Klenerman, D.Open in Google Scholar

Inappropriate aggregation of TAR DNA-binding protein 43 (TDP-43) is a hallmark of motor neuron disease (MND). Current methods for quantifying heterogeneous aggregate populations in biofluids are limited, precluding their routine use in diagnosis and disease monitoring. Single molecule microscopy methods overcome these limitations to deliver quantitative morphological and compositional fingerprinting of molecular assemblies containing TDP-43. Here, we demonstrate the application of such methods to extracts from donor brain tissues. We show the number and morphology of aggregates derived from frontal cortex and cerebellar samples is sufficient to distinguish MND donors from neurologically normal controls, as well as between different MND cohorts. In addition, we compare proteomic and microscopic compositional profiles, demonstrating how complementary insights delivered by each technique can enhance our understanding of disease mechanisms. These single molecule assays will inform future diagnostic and stratification technologies, improving our ability to deliver patient care in a timely and targeted manner.

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