C9orf72-SMCR8 complex (CSW complex)

The C9orf72-SMCR8 complex, often associated with WDR41 to form the C9orf72-SMCR8-WDR41 (CSW) complex, is a critical regulator of intracellular membrane trafficking and autophagy (Tang et al., 2020) [3.1.2]. It contains DENN (Differently Expressed in Normal and Neoplastic cells) domains and acts as a guanine nucleotide exchange factor (GEF) or GTPase-activating protein (GAP) for various Rab and Arf GTPases, such as Rab8a, Rab11a, and Arf1, thereby coordinating vesicle transport and lysosomal homeostasis (Sellier et al., 2016; Tang et al., 2020) [2.4.1, 3.1.2]. Mutations in the C9orf72 gene, specifically hexanucleotide repeat expansions (HRE), are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (DeJesus-Hernandez et al., 2011) [2.1.1]. These mutations lead to both a loss of the functional complex and a toxic gain of function through the formation of RNA foci and dipeptide repeat proteins (DPRs) (Zhang et al., 2018) [2.1.3]. Therapeutic strategies have primarily focused on antisense oligonucleotides (ASOs) like BIIB078 and WVE-004 to reduce toxic products, though recent clinical failures have shifted interest toward restoring the complex's normal function or targeting downstream consequences like LINE-1 activation and neuroinflammation (Wave Life Sciences, 2023; Biogen, 2022) [3.4.4, 3.5.5].

Other names

C9orf72-SMCR8-WDR41 complexCSW complexC9orf72-SMCR8 heterodimerC9orf72-SMCR8-WDR41 heterotrimerChromosome 9 open reading frame 72-Smith-Magenis syndrome chromosome region candidate 8 complex

Antisense oligonucleotides (ASOs) target the C9orf72 mRNA to reduce toxic RNA foci and dipeptide repeat proteins (DPRs). Experimental small molecules aim to modulate the complex's GTPase-activating protein (GAP) or guanine nucleotide exchange factor (GEF) activity to restore normal membrane trafficking and autophagy (ResearchGate, 2023) [2.3.1].