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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\u2013Magenis chromosome regions 8 (SMCR8) and WD repeat\u2010containing 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\n                      <jats:italic>C9ORF72<\/jats:italic>\n                      mutations have neuroinflammation phenotype. Recent studies indicate that C9ORF72 regulates trafficking and lysosomal degradation of inflammatory mediators, including toll\u2010like 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\n                      <jats:italic>C9ORF72<\/jats:italic>\n                      mutations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15255-fig-0005-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  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