C9orf72, a gene encoding a 54-kDa protein of initially unknown function, is highly expressed in the central nervous system [4]. It is involved in multiple cellular processes such as autophagy, membrane trafficking, and immune response [2]. The protein forms a complex with SMCR8 and WDR41, potentially acting as GTPase activating proteins [2].

The discovery that repeat expansions in C9orf72 are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized the understanding of these diseases [1]. Three main disease mechanisms have been proposed: loss of function of the C9orf72 protein, and toxic gain of function from C9orf72 repeat RNA or dipeptide repeat proteins produced by repeat-associated non-ATG translation [1]. C9orf72 deficiency in mice results in exaggerated inflammatory responses, indicating its role in regulating inflammatory outputs, likely through trafficking and lysosomal degradation of inflammatory mediators like toll-like receptors (TLRs) and STING [3].

In conclusion, C9orf72 is a multifunctional gene involved in various cellular processes. Studies using mouse models, especially those with C9orf72 deficiency, have been crucial in revealing its role in the pathogenesis of neurodegenerative diseases such as ALS and FTD, mainly through its impact on cellular functions and inflammatory responses [1,3].

References:

1. Balendra, Rubika, Isaacs, Adrian M. . C9orf72-mediated ALS and FTD: multiple pathways to disease. In Nature reviews. Neurology, 14, 544-558. doi:10.1038/s41582-018-0047-2. https://pubmed.ncbi.nlm.nih.gov/30120348/

2. Jiang, Lan, Zhang, Tizhong, Lu, Kefeng, Qi, Shiqian. 2021. The progress in C9orf72 research: ALS/FTD pathogenesis, functions and structure. In Small GTPases, 13, 56-76. doi:10.1080/21541248.2021.1892443. https://pubmed.ncbi.nlm.nih.gov/33663328/

3. Pang, Weilun, Hu, Fenghua. 2020. Cellular and physiological functions of C9ORF72 and implications for ALS/FTD. In Journal of neurochemistry, 157, 334-350. doi:10.1111/jnc.15255. https://pubmed.ncbi.nlm.nih.gov/33259633/

4. Xu, Xingfeng, Su, Yan, Zou, Zhenyou, Zhou, Yali, Yan, Jianguo. 2021. Correlation between C9ORF72 mutation and neurodegenerative diseases: A comprehensive review of the literature. In International journal of medical sciences, 18, 378-386. doi:10.7150/ijms.53550. https://pubmed.ncbi.nlm.nih.gov/33390807/