Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons
| Autor: | Gabriel R. Linares, Justin K. Ichida, Yingxiao Shi, Brandon B Ge, Yichen Li, Jacob Komberg, R. Jeroen Pasterkamp, Davide Trotti, Valerie Hennes, Leonard H. van den Berg, Nicole Koutsodendris, Jason A. Chen, Kaitlin P. Sandor, Vamshidhar R. Vangoor, Louise Menendez, Amy R. Nelson, Michael E. Ward, Tze-Yuan Cheng, Yaoming Wang, Phillip E. Woolwine, Wen-Hsuan Chang, Ketharini Senthilkumar, Kim A. Staats, Mickey Huang, Carina Seah, Alice Zhang, Chris Grunseich, Esther Y. Son, Eric Hendricks, Michael J. Cowan, Paul R. August, Kassandra Kisler, Shih Jong J. Lee, Marcelo P. Coba, Shu Ting Hung, Shaoyu Lin, Brent Wilkinson, N. Wisniewski, Berislav V. Zlokovic, Tohru Sugawara, T. Grant Belgard, Victor Hanson-Smith, Xinmei Wen |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Excitotoxicity Endosomes Haploinsufficiency Biology medicine.disease_cause Biochemistry General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences C9orf72 medicine Animals Humans Amyotrophic lateral sclerosis rab5 GTP-Binding Proteins Motor Neurons DNA Repeat Expansion C9orf72 Protein Biochemistry Genetics and Molecular Biology(all) Neurodegeneration Amyotrophic Lateral Sclerosis Glutamate receptor Neurodegenerative Diseases General Medicine medicine.disease Introns Cell biology Disease Models Animal 030104 developmental biology Gene Expression Regulation Frontotemporal Dementia Mutation Nerve Degeneration Trinucleotide repeat expansion Peptides Frontotemporal dementia Genetics and Molecular Biology(all) |
| Zdroj: | Nature Medicine, 24(3), 313. Nature Publishing Group |
| ISSN: | 1078-8956 |
| Popis: | An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the pathogenic mechanism of this repeat remains unclear. Using human induced motor neurons (iMNs), we found that repeat-expanded C9ORF72 was haploinsufficient in ALS. We found that C9ORF72 interacted with endosomes and was required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion reduced C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors, leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion. Thus, cooperativity between gain- and loss-of-function mechanisms led to neurodegeneration. Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescued patient neuron survival and ameliorated neurodegenerative processes in both gain- and loss-of-function C9ORF72 mouse models. Thus, modulating vesicle trafficking was able to rescue neurodegeneration caused by the C9ORF72 repeat expansion. Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS and FTD. |
| Databáze: | OpenAIRE |
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