Improved detection of pre-symptomatic, non-central nervous system TDP-43 pathology in amyotrophic lateral sclerosis using RNA aptamer

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

Abstract A recently developed TDP-43 RNA aptamer (TDP-43 APT ) with greater sensitivity and specificity for detecting pathological TDP-43, compared to currently available antibodies, has revealed novel pathologies in ALS, including early nuclear aggregation preceding disease symptoms. Moreover, whilst ALS traditionally been considered a of the central nervous system (CNS), non-CNS manifestations are gaining increasing awareness. Employing an antibody approach detect pathologically phosphorylated we previously uncovered pre-symptomatic, systemic pathology archived tissue, taken during life. Here, using two tools, (i) identify (ii) situ hybridisation probes directed splice target ( Stathmin-2 demonstrate concurrent loss function, re-examined tissues from variety organ systems this cohort ante-mortem tissue people who went on develop ALS. Amongst organs evidence aggregation, loss-of-function, occurring prior motor symptom onset, were colon, skin, muscle, blood vessels, gallbladder, lymph nodes. Cell types affected include sebocytes, endothelial cells, peripheral neuronal dendritic chondrocytes - all cells shared cell linage neural crest, implying neurodevelopmentally-defined cell-type specific predisposition pathology. This predisposition, along identified mobile, circulating inflammatory (T-cells macrophages) may help guide early, pre-symptomatic biopsy biomarker development. Our findings extend number outside CNS symptoms, showing is common feature affecting that readily accessible biopsy. We propose skin gastro-intestinal tract provide most promising potential ease biopsy, applications diagnosis monitoring emergence amongst general at-risk populations. Graphical Abstract: detects patients diagnosis. A) Cartoon depicting with, without, detected by aptamer. B) Timeline years onset could be node, gastrointestinal tissues.

Language: Английский

Fibril-seeded animal models of synucleinopathies: pathological mechanisms, disease modeling, and therapeutic implications

Neuroscience Research, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Accumulating evidence suggests that prion-like spread of misfolded α-Synuclein (αSyn) underlies the pathological progression Lewy body diseases (LBD). Animal models injected with αSyn preformed fibrils (PFFs) have provided strong for prion hypothesis in LBD. Moreover, PFFs can be administered to various hosts and regions, contributing elucidation mechanisms disease modeling. These also been used identify biomarkers develop new disease-modifying therapies In contrast, it remains unknown how properties contribute pathogenesis multiple system atrophy (MSA). Recent studies indicate conformationally distinct induce different features animals, supporting strain hypothesis, which conformational variations clinicopathological heterogeneity synucleinopathies. However, study disease-specific modeling is still its early stages. This review aims highlight recent advances fibril-seeded animal an emphasis on their unique utility exploring identifying novel therapies. addition, I discuss future directions refining these light emerging

Language: Английский