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Small molecules targeting ARF1 interaction with C9orf72:SMCR8:WDR41 complexes suppress its overactivation implicated
Biorxiv : the Preprint Server for Biology
|July 10, 2026
Summary
Researchers identified a new drug candidate, SCC944, that targets the ARF1-CSW interaction. This discovery offers a potential new therapeutic strategy for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- The hexanucleotide repeat expansion in the *C9orf72* gene is the primary genetic driver of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
- The C9orf72 protein complex (CSW) acts as a GTPase-activating protein (GAP) for ARF1 and RAB small GTPases, suggesting ARF1 dysregulation in ALS/FTD.
- A lack of small molecules targeting ARF1-CSW interactions has hindered therapeutic development.
Purpose of the Study:
- To identify small molecules that modulate ARF1-CSW interactions for potential ALS/FTD therapeutics.
- To investigate the role of ASAP1 phosphorylation in ALS/FTD pathogenesis.
- To characterize the mechanism of action of a novel ARF1-CSW modulator.
Main Methods:
- Analysis of ASAP1 phosphorylation in human motor cortex from ALS patients.
- Expression studies of *C9orf72* and its effects on Golgi apparatus.
- Computer-aided drug design and high-throughput *in-silico* screening to identify ARF1-CSW modulators.
- Biochemical assays to assess SCC944 binding to ARF1 and its effect on GTP-bound ARF1 levels.
- Cellular studies to evaluate SCC944's impact on organelle organization and protein trafficking.
Main Results:
- Tyrosine-phosphorylated ASAP1 was upregulated in the motor cortex of sporadic ALS and *C9orf72*-mutation ALS patients.
- *C9orf72* expression mimicked some effects of the ARF1 inhibitor brefeldin A on the Golgi apparatus.
- SCC944 was identified as a novel ARF1-CSW modulator that binds ARF1 and reduces GTP-bound ARF1.
- SCC944 induced ARF1-dependent alterations in Golgi, microtubule, and mitochondrial organization, with a distinct protein trafficking profile compared to brefeldin A.
Conclusions:
- The study identified the first small molecule, SCC944, targeting the ARF1-CSW interaction.
- Upregulation of ASAP1 phosphorylation suggests its involvement in ALS/FTD.
- ARF1 modulation represents a promising therapeutic avenue for ALS/FTD.
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