Microglia in C9orf72–associated amyotrophic lateral sclerosis: More or less active?

a t e r a l s c l e r o s i s ( A L S ) i s 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).