Longitudinal transcriptomic analysis of altered pathways in a CHMP2Bintron5-based model of ALS-FTD

NEUROBIOLOGY OF DISEASE

卷:136

Article

Waegaert, Robin¹  Dirrig-Grosch, Sylvie¹  Parisot, Florian¹  Keime, Celine²  Henriques, Alexandre¹  Loeffler, Jean-Philippe¹  Rene, Frederique¹ 

[1] Univ Strasbourg, INSERM Mecanismes Cent & Peripher Neurodegeneresc, 11 Rue Humann,Batiment 3, F-67000 Strasbourg, France

[2] Univ Strasbourg, Inst Genet & Biol Mol & Cellulaire, UMR7104, INSERM U1258, 1 Rue Laurent Fries, F-67400 Illkirch Graffenstaden, France

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

DOI  :  10.1016/j.nbd.2019.104710

来源: Elsevier

【 摘 要 】

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-Fib linked to the CHMP2B gene, we performed a whole transcriptomic study on lumbar spinal cord from CHMP2B(intron5) 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 CHMP2B(intron5) mice with the one of symptomatic SOD1(G86R) 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 CHMP2B(intron5) -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.