Details

Autor(en) / Beteiligte

• Aoki, Yoshitsugu
• Manzano, Raquel
• Lee, Yi
• Dafinca, Ruxandra
• Aoki, Misako
• Douglas, Andrew G L
• Varela, Miguel A
• Sathyaprakash, Chaitra
• Scaber, Jakub
• Barbagallo, Paola
• Vader, Pieter
• Mäger, Imre
• Ezzat, Kariem
• Turner, Martin R
• Ito, Naoki
• Gasco, Samanta
• Ohbayashi, Norihiko
• El Andaloussi, Samir
• Takeda, Shin'ichi
• Fukuda, Mitsunori
• Talbot, Kevin
• Wood, Matthew J A

Titel

C9orf72 and RAB7L1 regulate vesicle trafficking in amyotrophic lateral sclerosis and frontotemporal dementia

Ist Teil von

• Brain (London, England : 1878), 2017-04, Vol.140 (4), p.887-897

Ort / Verlag

England

Erscheinungsjahr

2017

Link zum Volltext

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• A non-coding hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), however, the precise molecular mechanism by which the C9orf72 hexanucleotide repeat expansion directs C9ALS/FTD pathogenesis remains unclear. Here, we report a novel disease mechanism arising due to the interaction of C9ORF72 with the RAB7L1 GTPase to regulate vesicle trafficking. Endogenous interaction between C9ORF72 and RAB7L1 was confirmed in human SH-SY5Y neuroblastoma cells. The C9orf72 hexanucleotide repeat expansion led to haploinsufficiency resulting in severely defective intracellular and extracellular vesicle trafficking and a dysfunctional trans-Golgi network phenotype in patient-derived fibroblasts and induced pluripotent stem cell-derived motor neurons. Genetic ablation of RAB7L1or C9orf72 in SH-SY5Y cells recapitulated the findings in C9ALS/FTD fibroblasts and induced pluripotent stem cell neurons. When C9ORF72 was overexpressed or antisense oligonucleotides were targeted to the C9orf72 hexanucleotide repeat expansion to upregulate normal variant 1 transcript levels, the defective vesicle trafficking and dysfunctional trans-Golgi network phenotypes were reversed, suggesting that both loss- and gain-of-function mechanisms play a role in disease pathogenesis. In conclusion, we have identified a novel mechanism for C9ALS/FTD pathogenesis highlighting the molecular regulation of intracellular and extracellular vesicle trafficking as an important pathway in C9ALS/FTD pathogenesis.