Table 3.

Potential Cul3-involved pathways in NDDs.

Up/Down-stream target	Characteristics	Protein–protein interaction	Potential treatment strategy
RhoA (23)	A substrate of Cul3 ligase which controls neurite outgrowth.	Cul3 deficiency dysregulates neuron cytoskeleton and neurogenesis through increased RhoA levels.	Cortical neurons treated with RhoA inhibitor (Rhosin) showed rescued dendritic length and neural network activity.
eIF4G1 (41)	Cap-dependent translation protein.	Cul3 deficiency increases eIF4G1 to promote cap-dependent translation.	Inhibition (by 4EGI-1) alleviates ASD-associated cellular and behavioral deficits.
Smyd3 (26)	A histone methyltransferase is involved in gene transcription.	Cul3 deficiency upregulates Smyd3 to further inhibit NMDAR function.	Inhibition (by BCI-121) or knockdown of Smyd3 overcomes Cul3 deficient-caused ASD.
COP9 signalosome (CSN) (67)	Member of the conserved 26S proteasome degradation pathway.	CSN restricts dendritic branching via Cul3-dependent degradation of the actin cross-linking BTB-domain protein Kelch. Loss of Cul3 and overexpression of Kelch stimulates dendritic branching.	Targeting the CSN-Cul3-Kelch pathway may play a role in intellectual disability and neurodegenerative diseases.
Plastin3 (Pls3) (25)	Involves in neuronal migration.	Cul3 deficiency increases Pls3 and inhibits neuronal migration.	/
Insomniac (Inc) (24)	A putative adaptor of the Cul3 ubiquitin ligase complex.	Cul3 and Inc. are required for rapid ubiquitination of postsynaptic targets and retrograde homeostatic signaling.	Targeting synaptic homeostatic plasticity may be a potential treatment for ASD.