Abundant transcriptomic alterations in the human cerebellum of patients with a C9orf72 repeat expansion

Evan Udine, Mariely DeJesus-Hernandez, Shulan Tian, Sofia Pereira das Neves, Richard Crook, Ni Cole A. Finch, Matthew C. Baker, Cyril Pottier, Neill R. Graff-Radford, Bradley F. Boeve, Ronald C. Petersen, David S. Knopman, Keith A. Josephs, Björn Oskarsson, Sandro Da Mesquita, Leonard Petrucelli, Tania F. Gendron, Dennis W. Dickson, Rosa Rademakers, Marka van Blitterswijk

Research output: Contribution to journalArticlepeer-review


The most prominent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a repeat expansion in the gene C9orf72. Importantly, the transcriptomic consequences of the C9orf72 repeat expansion remain largely unclear. Here, we used short-read RNA sequencing (RNAseq) to profile the cerebellar transcriptome, detecting alterations in patients with a C9orf72 repeat expansion. We focused on the cerebellum, since key C9orf72-related pathologies are abundant in this neuroanatomical region, yet TDP-43 pathology and neuronal loss are minimal. Consistent with previous work, we showed a reduction in the expression of the C9orf72 gene and an elevation in homeobox genes, when comparing patients with the expansion to both patients without the C9orf72 repeat expansion and control subjects. Interestingly, we identified more than 1000 alternative splicing events, including 4 in genes previously associated with ALS and/or FTLD. We also found an increase of cryptic splicing in C9orf72 patients compared to patients without the expansion and controls. Furthermore, we demonstrated that the expression level of select RNA-binding proteins is associated with cryptic splice junction inclusion. Overall, this study explores the presence of widespread transcriptomic changes in the cerebellum, a region not confounded by severe neurodegeneration, in post-mortem tissue from C9orf72 patients.

Original languageEnglish (US)
Article number73
JournalActa neuropathologica
Issue number1
StatePublished - Jun 2024


  • Amyotrophic lateral sclerosis
  • C9orf72
  • Cryptic exons
  • Frontotemporal lobar degeneration
  • Transcriptomics

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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