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Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs.

Matthew J KeussPeter HarleyEugeni M RyadnovRachel E JacksonMatteo ZanovelloOscar G WilkinsSimone BarattucciPuja R MehtaMarcio G OliveiraJoanna E ParkesAparna SinhaAndrés F Correa-SánchezPeter L OliverElizabeth M C FisherGiampietro SchiavoMala ShahJuan BurronePietro Fratta
Published in: bioRxiv : the preprint server for biology (2024)
TDP-43 loss of function induces multiple splicing changes, including a cryptic exon in the amyotrophic lateral sclerosis and fronto-temporal lobar degeneration risk gene UNC13A, leading to nonsense-mediated decay of UNC13A transcripts and loss of protein. UNC13A is an active zone protein with an integral role in coordinating pre-synaptic function. Here, we show TDP-43 depletion induces a severe reduction in synaptic transmission, leading to an asynchronous pattern of network activity. We demonstrate that these deficits are largely driven by a single cryptic exon in UNC13A. Antisense oligonucleotides targeting the UNC13A cryptic exon robustly rescue UNC13A protein levels and restore normal synaptic function, providing a potential new therapeutic approach for ALS and other TDP-43-related disorders.
Keyphrases
  • amyotrophic lateral sclerosis
  • prefrontal cortex
  • traumatic brain injury
  • binding protein
  • genome wide
  • risk assessment
  • nucleic acid
  • transcription factor
  • human health