RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides with STMN-2 cryptic splicing and precedes clinical manifestation in ALS.

Autor: Spence H; Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK., Waldron FM; Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK., Saleeb RS; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, UK.; IRR Chemistry Hub, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK., Brown AL; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK., Rifai OM; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK., Gilodi M; RNA System Biology Lab, Instituto Italiano di Tecnologia, Genoa, Italy., Read F; Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK., Roberts K; Department of Pathology, NHS Grampian Tissue Biorepository, Aberdeen, UK., Milne G; Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK., Wilkinson D; Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK., O'Shaughnessy J; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, UK.; IRR Chemistry Hub, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK., Pastore A; The Maurice Wohl Institute, King's College London, London, UK., Fratta P; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK., Shneider N; Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, New York, NY, USA., Tartaglia GG; RNA System Biology Lab, Instituto Italiano di Tecnologia, Genoa, Italy., Zacco E; RNA System Biology Lab, Instituto Italiano di Tecnologia, Genoa, Italy., Horrocks MH; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, UK. mathew.horrocks@ed.ac.uk.; IRR Chemistry Hub, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK. mathew.horrocks@ed.ac.uk., Gregory JM; Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK. jenna.gregory@abdn.ac.uk.; Department of Pathology, NHS Grampian Tissue Biorepository, Aberdeen, UK. jenna.gregory@abdn.ac.uk.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2024 Mar 05; Vol. 147 (1), pp. 50. Date of Electronic Publication: 2024 Mar 05.
DOI: 10.1007/s00401-024-02705-1
Abstrakt: TDP-43 is an aggregation-prone protein which accumulates in the hallmark pathological inclusions of amyotrophic lateral sclerosis (ALS). However, the analysis of deeply phenotyped human post-mortem samples has shown that TDP-43 aggregation, revealed by standard antibody methods, correlates poorly with symptom manifestation. Recent identification of cryptic-splicing events, such as the detection of Stathmin-2 (STMN-2) cryptic exons, are providing evidence implicating TDP-43 loss-of-function as a potential driving pathomechanism but the temporal nature of TDP-43 loss and its relation to the disease process and clinical phenotype is not known. To address these outstanding questions, we used a novel RNA aptamer, TDP-43 APT , to detect TDP-43 pathology and used single molecule in situ hybridization to sensitively reveal TDP-43 loss-of-function and applied these in a deeply phenotyped human post-mortem tissue cohort. We demonstrate that TDP-43 APT identifies pathological TDP-43, detecting aggregation events that cannot be detected by classical antibody stains. We show that nuclear TDP-43 pathology is an early event, occurring prior to cytoplasmic accumulation and is associated with loss-of-function measured by coincident STMN-2 cryptic splicing pathology. Crucially, we show that these pathological features of TDP-43 loss-of-function precede the clinical inflection point and are not required for region specific clinical manifestation. Furthermore, we demonstrate that gain-of-function in the form of extensive cytoplasmic accumulation, but not loss-of-function, is the primary molecular correlate of clinical manifestation. Taken together, our findings demonstrate implications for early diagnostics as the presence of STMN-2 cryptic exons and early TDP-43 aggregation events could be detected prior to symptom onset, holding promise for early intervention in ALS.
(© 2024. The Author(s).)
Databáze: MEDLINE
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