TY - UNPB
T1 - RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides withSTMN-2cryptic splicing and precedes clinical manifestation in ALS
AU - Spence, Holly
AU - Waldron, Fergal M.
AU - Saleeb, Rebecca S.
AU - Brown, Anna-Leigh
AU - Rifai, Olivia M.
AU - Gilodi, Martina
AU - Read, Fiona
AU - Roberts, Kristine
AU - Milne, Gillian
AU - Wilkinson, Debbie
AU - O’Shaughnessy, Judi
AU - Pastore, Annalisa
AU - Fratta, Pietro
AU - Shneider, Neil
AU - Tartaglia, Gian Gaetano
AU - Zacco, Elsa
AU - Horrocks, Mathew H.
AU - Gregory, Jenna M.
PY - 2023/10/27
Y1 - 2023/10/27
N2 - 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 in amyotrophic lateral sclerosis (ALS). However, the temporal nature of TDP-43 loss and its relation to clinical phenotype is not known. Here, we used a novel RNA aptamer to detect TDP-43 aggregation and used single molecule ISH to sensitively reveal TDP-43 loss-of-function, applying these methods in a deeply-phenotyped human post-mortem tissue cohort. We show that nuclear TDP-43 pathology is an early event, that coincides with STMN-2 cryptic splicing. 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, but not loss-of-function, is the primary molecular correlate of clinical manifestation. Taken together, our findings demonstrate implications for early diagnostics and intervention prior to symptom onset in ALS.
AB - 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 in amyotrophic lateral sclerosis (ALS). However, the temporal nature of TDP-43 loss and its relation to clinical phenotype is not known. Here, we used a novel RNA aptamer to detect TDP-43 aggregation and used single molecule ISH to sensitively reveal TDP-43 loss-of-function, applying these methods in a deeply-phenotyped human post-mortem tissue cohort. We show that nuclear TDP-43 pathology is an early event, that coincides with STMN-2 cryptic splicing. 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, but not loss-of-function, is the primary molecular correlate of clinical manifestation. Taken together, our findings demonstrate implications for early diagnostics and intervention prior to symptom onset in ALS.
UR - https://doi.org/10.1101/2023.10.24.563701
U2 - 10.1101/2023.10.24.563701
DO - 10.1101/2023.10.24.563701
M3 - Preprint
BT - RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides withSTMN-2cryptic splicing and precedes clinical manifestation in ALS
PB - bioRxiv
ER -