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

• Published in: Acta neuropathologica Vol. 147; no. 1; p. 73
• Main Authors: Udine, Evan, DeJesus-Hernandez, Mariely, Tian, Shulan, das Neves, Sofia Pereira, Crook, Richard, Finch, NiCole A., Baker, Matthew C., Pottier, Cyril, Graff-Radford, Neill R., Boeve, Bradley F., Petersen, Ronald C., Knopman, David S., Josephs, Keith A., Oskarsson, Björn, Da Mesquita, Sandro, Petrucelli, Leonard, Gendron, Tania F., Dickson, Dennis W., Rademakers, Rosa, van Blitterswijk, Marka
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-06-2024; Springer Nature B.V
• Subjects: Alternative splicing; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Anatomy; C9orf72 Protein - genetics; C9orf72 Protein - metabolism; Cerebellum; Cerebellum - pathology; DNA Repeat Expansion - genetics; Frontotemporal dementia; Frontotemporal Lobar Degeneration - genetics; Frontotemporal Lobar Degeneration - metabolism; Frontotemporal Lobar Degeneration - pathology; Gene Expression Profiling; Genes; Homeobox; Humans; Medicine; Medicine & Public Health; Neurodegeneration; Neurosciences; Original Paper; Pathology; RNA-binding protein; Transcriptome; Transcriptomes; Transcriptomics; Cryptic exons; Amyotrophic lateral sclerosis; Frontotemporal lobar degeneration; Transcriptomics; C9orf72
• ISSN: 0001-6322; 1432-0533; 1432-0533
• DOI: 10.1007/s00401-024-02720-2

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.