Longitudinal transcriptomic analysis of altered pathways in a CHMP2B intron5-based model of ALS-FTD

Neurobiol Dis. 2020 Mar;136:104710. doi: 10.1016/j.nbd.2019.104710. Epub 2019 Dec 16.


Amyotrophic lateral sclerosis and frontotemporal dementia are two neurodegenerative diseases with currently no cure. These two diseases share a clinical continuum with overlapping genetic causes. Mutations in the CHMP2B gene are found in patients with ALS, FTD and ALS-FTD. To highlight deregulated mechanisms occurring in ALS-FTD linked to the CHMP2B gene, we performed a whole transcriptomic study on lumbar spinal cord from CHMP2Bintron5 mice, a model that develops progressive motor alterations associated with dementia symptoms reminiscent of both ALS and FTD. To gain insight into the transcriptomic changes taking place during disease progression this study was performed at three stages: asymptomatic, symptomatic and end stage. We showed that before appearance of motor symptoms, the major disrupted mechanisms were linked with the immune system/inflammatory response and lipid metabolism. These processes were progressively replaced by alterations of neuronal electric activity as motor symptoms appeared, alterations that could lead to motor neuron dysfunction. To investigate overlapping alterations in gene expression between two ALS-causing genes, we then compared the transcriptome of symptomatic CHMP2Bintron5 mice with the one of symptomatic SOD1G86R mice and found the same families deregulated providing further insights into common underlying dysfunction of biological pathways, disrupted or disturbed in ALS. Altogether, this study provides a database to explore potential new candidate genes involved in the CHMP2Bintron5-based pathogenesis of ALS, and provides molecular clues to further understand the functional consequences that diseased neurons expressing CHMP2B mutant may have on their neighbor cells.

Keywords: Amyotrophic lateral sclerosis; Frontotemporal dementia; Inflammation; Ion transporters; Lipid metabolism; Mouse models; SOD1(G86R); Transcriptomic analysis CHMP2B(intron5).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Disease Models, Animal*
  • Endosomal Sorting Complexes Required for Transport / biosynthesis
  • Endosomal Sorting Complexes Required for Transport / genetics*
  • Frontotemporal Dementia / genetics*
  • Frontotemporal Dementia / metabolism
  • Frontotemporal Dementia / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics*
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Superoxide Dismutase-1 / genetics*
  • Transcriptome / genetics*


  • CHMP2B protein, mouse
  • Endosomal Sorting Complexes Required for Transport
  • Nerve Tissue Proteins
  • Sod1 protein, mouse
  • Superoxide Dismutase-1