Breakdown in the synaptic vesicle cycle defines early and reversible cortical pathogenesis in ALS
Laszlo, Z. I.; Sanchez-Avila, A.; McFarlane, A.; van der Hoorn, D.; San Gil, R.; Spires-Jones, T. L.; Gillingwater, T. H.; Walker, A. K.; Henstridge, C. M.
Show abstract
Synaptic failure is considered an early driver of Amyotrophic Lateral Sclerosis (ALS), yet identifying the molecular events initiating synaptic decline remains challenging in end-stage human tissue. Here, we exploit the late involvement of the primary visual cortex (Brodmann Area 17 (BA17)) to investigate early disease-associated changes in human ALS. Structural analyses revealed neuropil compaction, presynaptic terminal shrinkage, and synaptic degeneration despite preservation of local neuronal populations. Deep synaptoneurosome proteomics identified a regional signature characterised by disruption of presynaptic vesicle cycling, which closely resembles early pathological changes observed in the inducible human TDP-43 rNLS8 mouse model. Importantly, suppression of TDP-43 expression in vivo restored these proteomic alterations, highlighting recovery of presynaptic vesicle machinery within preserved synaptic structures. Together, these findings reveal early synaptic pathology as a distinct and potentially reversible stage of ALS neurodegeneration.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication 95%
- Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy 95%
- Structural polymorphism of ex-vivo ALECT2 amyloid fibrils revealed by cryo-EM 94%
Similar papers in this journal
- Single-cell transcriptomic landscape of the neuroimmune compartment in amyotrophic lateral sclerosis brain and spinal cord 94%
- Selective Vulnerability of Tripartite Synapses in Amyotrophic Lateral Sclerosis. 94%
- Nuclear depletion of RNA binding protein ELAVL3 (HuC) in sporadic and familial amyotrophic lateral sclerosis 93%
Similar papers in this journal
- TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration 94%
- Circulating miR-181 is a prognostic biomarker for amyotrophic lateral sclerosis 93%
- Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation 93%
Similar papers in this journal
- Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia 95%
- TDP-43-stratified single-cell proteomic profiling of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis 95%
- ALS molecular subtypes are a combination of cellular, genetic, and pathological features learned by deep multiomics classifiers 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.