期刊
SCIENCE ADVANCES
卷 7, 期 15, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abg3013
关键词
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资金
- KU Leuven [C1-C14-17-107]
- Opening the Future Fund (KU Leuven)
- Alzheimer Research Foundation (SAO-FRA) [2017/023]
- Flemish Government [135043]
- Fund for Scientific Research Flanders (FWO Vlaanderen) [G.0909.15, G0F8516N, G0B2819N]
- Agency for Innovation by Science and Technology (IWT) [135043, 150031]
- European E-Rare-3 project INTEGRALS
- ALS Liga Belgie
- National Lottery of Belgium
- KU Leuven fund Een Hart voor ALS
- KU Leuven fund Laeversfonds voor ALS Onderzoek
- KU Leuven fund Valery Perrier Race against ALS Fund
- E. von Behring Chair for Neuromuscular Disorders
- UK Medical Research Council [MC_U105178790]
- EMBO Long-Term Fellowship
- Medical Research Council [MR/R001162/1]
- Motor Neurone Disease Association [MR/R001162/1]
- Research Foundation-Flanders (FWO-Vlaanderen) [1165119 N]
- UK Medical Research Council
- Alzheimer's Research UK
- Alzheimer's Society
- MRC [MC_U105178790, UKDRI-4003] Funding Source: UKRI
A hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of ALS and FTD. This mutation impairs microtubule-based transport in neurons, leading to potential therapeutic strategies targeting axonal transport machinery. Arginine-rich DPRs inhibit axonal trafficking by interacting with motor complexes and microtubules.
A hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this mutation leads to these neurodegenerative diseases remains unclear. Here, we show using patient stem cell-derived motor neurons that the repeat expansion impairs microtubule-based transport, a process critical for neuronal survival. Cargo transport defects are recapitulated by treating neurons from healthy individuals with proline-arginine and glycine-arginine dipeptide repeats (DPRs) produced from the repeat expansion. Both arginine-rich DPRs similarly inhibit axonal trafficking in adult Drosophila neurons in vivo. Physical interaction studies demonstrate that arginine-rich DPRs associate with motor complexes and the unstructured tubulin tails of microtubules. Single-molecule imaging reveals that microtubule-bound arginine-rich DPRs directly impede translocation of purified dynein and kinesin-1 motor complexes. Collectively, our study implicates inhibitory interactions of arginine-rich DPRs with axonal transport machinery in C9orf72-associated ALS/FTD and thereby points to potential therapeutic strategies.
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