Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are linked neurodegenerative disorders characterized by synaptic dysfunction and TDP-43 pathology. A hexanucleotide repeat expansion (HRE) in the C9ORF72 (C9) gene is the most common genetic cause of FTD and ALS. Despite this, synapse-specific molecular mechanisms that drive disease pathogenesis in C9-FTD remain incompletely defined. The authors sought to address this gap by profiling molecular alterations specifically within synaptic compartments using an integrated multi-omic strategy.
The study performed integrated multi-omic profiling of synaptosomes enriched from two complementary sources: postmortem frontal cortex from patients with C9-FTD and synaptosomes prepared from patient-derived induced pluripotent stem cell (iPSC)–derived cortical neurons. This combined strategy was intended to capture synapse-enriched proteomic and transcriptomic changes in human brain tissue and to assess whether disease-relevant changes are recapitulated in an iPSC neuronal model.
Details on the exact number of postmortem samples, iPSC lines, or additional experimental parameters (for example, cohort demographics, synaptosome isolation protocol specifics, and statistical correction methods beyond p<0.05) were not reported in the provided source excerpt.
Proteomic profiling of frontal cortex–derived synaptosomes identified 1,324 differentially abundant proteins (p<0.05). Differentially abundant proteins were enriched in pathways that regulate synaptic vesicle transport and synapse organization, indicating widespread perturbation of structural and trafficking components critical for synaptic function. These protein-level changes implicate both the machinery for neurotransmitter release and the organization of pre- and postsynaptic specializations in C9-FTD synapses.
The source excerpt does not provide specific protein names (other than later-mentioned cryptic exon–associated genes at the RNA level), effect directions for individual proteins, or detailed pathway enrichment statistics beyond the pathway themes reported.
Synaptosomal RNA sequencing of frontal cortex samples revealed 2,835 differentially expressed protein-coding genes, underscoring substantial transcriptome remodeling at the synapse in C9-FTD. The reported scale of transcript changes suggests that altered localization, stability, or local processing of mRNAs contributes to synaptic dysfunction in disease.
Specific lists of altered transcripts, fold changes, or gene ontology terms beyond the general characterization were not included in the provided excerpt.
C9-FTD iPSC-cortical neurons displayed reductions in excitatory and inhibitory postsynaptic markers. Functionally, these neurons exhibited progressive impairment of neuronal network activity, consistent with deficits in synaptic connectivity and signaling. Synaptosomes derived from these iPSC neurons recapitulated key molecular pathways observed in patient brain synaptosomes, demonstrating convergent dysregulation of synaptic signaling pathways across postmortem tissue and cellular models.
The excerpt does not report specific electrophysiological metrics, timeline of progressive impairment, or numbers of replicates used for network activity assays.
Comparative analyses revealed a divergence between protein-level and RNA-level alterations within diseased synapses. This discordance is consistent with disruption of the regulatory processes that link local RNA abundance to protein production or stability at synapses. Such decoupling could reflect altered mRNA transport, local translation, protein turnover, or other post-transcriptional regulatory mechanisms in C9-FTD.
Further mechanistic detail, including candidate regulators or experimental validation of disrupted coupling, was not reported in the provided excerpt.
Consistent with TDP-43 loss-of-function pathology, the authors identified cryptic exon (CE)–containing transcripts within C9-FTD frontal cortex–derived synaptosomes. Notably, CE-containing RNAs included transcripts of KALRN and STMN2, indicating that aberrantly spliced RNAs localize to synaptic compartments. This finding provides direct evidence that disease-associated mis-splicing produces localized RNA species that could perturb synaptic function.
The excerpt does not provide the frequency, relative abundance, or validation methods for these CE-containing transcripts beyond their detection in synaptosome RNA-seq.
Together, the reported results define convergent molecular pathways underlying synaptic dysfunction in C9-FTD by integrating proteomic and transcriptomic measurements from human brain synaptosomes and patient-derived neurons. Key conclusions are that synapse-enriched proteins and RNAs are broadly altered, that iPSC-derived models recapitulate aspects of the patient synaptic molecular signature, and that aberrant splicing products linked to TDP-43 pathology localize to synaptic compartments.
The source excerpt is truncated and does not report several important experimental details such as cohort sizes, full lists of altered proteins and transcripts, quantitative effect sizes, validation experiments, or statistical correction methods. Those details were not reported in the provided text and should be consulted in the full preprint for comprehensive evaluation.