Cellular and physiological functions of C9ORF72 and implications for ALS/FTD

Abstract

The hexanucleotide repeat expansion (HRE) in the C9ORF72 gene is the main cause of two tightly linked neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). HRE leads to not only a gain of toxicity from RNA repeats and dipeptide repeats but also reduced levels of C9ORF72 protein. However, the cellular and physiological functions of C9ORF72 were unknown until recently. Through proteomic analysis, Smith-Magenis chromosome regions 8 (SMCR8) and WD repeat-containing protein (WDR41) were identified as binding partners of C9ORF72. These three proteins have been shown to form a tight complex, but the exact functions of this complex remain to be characterized. Both C9ORF72 and SMCR8 contain a DENN domain, which has been shown to regulate the activities of small GTPases. The C9ORF72 complex has been implicated in many cellular processes, including vesicle trafficking, lysosome homeostasis, mTORC1 signaling , and autophagy. C9ORF72 deficiency in mice results in exaggerated inflammatory responses and human patients with C9ORF72 mutations have neuroinflammation phenotype. Recent studies indicate that C9ORF72 regulates trafficking and lysosomal degradation of inflammatory mediators, including toll-like receptors (TLRs) and STING, to affect inflammatory outputs. Further exploration of cellular and physiological functions of C9ORF72 will help dissect the pathological mechanism of ALS/FTD caused by C9ORF72 mutations.

Keywords: ALS; C9ORF72; FTD; SMCR8; WDR41; autophagy; inflammation; lysosome; mTORC1.

FIGURE 1

Summary of pathways affected by C9ORF72 HRE that lead to the development of ALS/FTD. Both loss of function of C9ORF72 and gain of toxicity from RNA foci and dipeptide repeat proteins contribute to the disease progression.

FIGURE 2

The C9ORF72 complex regulates lysosomal function. A) The C9ORF72 complex is cytosolic under nutrient-rich conditions but B) gets recruited to lysosomes under amino acid starvation conditions through the interaction between WDR41 and PQLC2. The C9ORF72 complex regulates several aspects of lysosomes including lysosome biogenesis, lysosomal enzyme activities, lysosome pH, lysosome reformation, autophagosome–lysosome fusion, lysosome–plasma membrane fusion, and mTORC1 signaling on lysosomal membrane.

FIGURE 3

The C9ORF72 complex regulates autophagy initiation and progression. A) The C9ORF72 complex acts downstream of the Rab1 GTPase to recruit the ULK1 complex to the phagophore during autophagy initiation. B) It also interacts with Rab8 and Rab39 GTPases, which, respectively, bind to OPTN and p62, proteins important for substrate delivery to autophagosomes. C,D) The C9ORF72 complex also interacts with Rab5 and Rab7, which play a role in autophagosome maturation and autophagosome–lysosome fusion.

FIGURE 4

The role of the C9ORF72 complex in the innate immune response. (A) C9ORF72 regulates inflammatory responses by affecting several cellular pathways, including endolysosomal trafficking, autophagy, and mTORC1 signaling. (B) Possible actions of the C9ORF72 complex in innate immune signaling. C9ORF72 may influence the transportation of antigens to immune receptors like TLRs; it may affect the mTORC1 activity after the immune receptors are activated; it may affect the degradation of the immune receptors inside the lysosomes; it might also affect lysosomal degradation and leakage of immune stimuli.