摘要Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron (MN) loss and muscle wasting,ultimately leading to death due to respiratory failure. A hexanucleotide (GGGGCC) repeat expansion (HRE)in C9orf72 is the most common genetic cause of ALS(C9-ALS) and frontotemporal dementia. C9orf72 HRE causes ALS through different mechanisms,which include reduced C9orf72 expression,the generation of RNA foci and dipeptide repeat proteins (DPRs),and TAR DNA-binding protein 43 (TDP-43) pathology.A large body of experimental work supports a role for microglial changes in C9-ALS. For example,human post-mortem analyses show microglial tissue infiltration,C9orf72 is strongly expressed in microglia,and loss of C9orf72 leads to lysosomal accumulation and altered pro-inflammatory responses in mice.Furthermore,recent single-cell transcriptomic analysis of human C9-ALS microglia reports an impaired transition of microglia towards a reactive cell state,which is supported by observations in C9-ALS organoid-derived microglia (oMG).